bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary results from two phase II studies of lenalidomide monotherapy in relapsed/refractory non-Hodgkin’s Lymphoma
Authors: Wiernik P. H. , Lossos I. S. , Justice G. , Zeldis J. B. , Takeshita K. , Pietronigro D. , Habermann T. M. , Witzig T. E.
Published: March 2020

17569

Background: Lenalidomide is an immunomodulatory drug of the IMiD class that has activity in multiple myeloma, myelodysplastic syndromes and chronic lymphocytic leukemia. We report preliminary results of two Phase II studies assessing the safety and efficacy of lenalidomide monotherapy in subjects with relapsed/refractory indolent or aggressive non-Hodgkin’s lymphoma (NHL). Methods: Subjects with indolent (study NHL-001) or aggressive (study NHL-002) relapsed/refractory NHL following ≥ 1 prior treatment regimen with measurable disease are eligible. Subjects receive 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continue therapy for 52 weeks as tolerated until disease progression. Response and progression are evaluated using cross sectional imaging by the NCI criteria. Results: 10 subjects (2 indolent (I), 8 aggressive (A)) of a planned 80 (40 in each study) have enrolled thus far. Median age is 66 (45–80) and 7 subjects are female. Indolent histology is follicular center lymphoma grade 1, 2 (n = 2) and aggressive histology diffuse large cell lymphoma (n = 7) and follicular center lymphoma grade 3 (n = 1). Median time from diagnosis to lenalidomide monotherapy is 2.9 years (1.1–10) and median number of prior treatment regimens per subject is 3 (1–6). Median duration of follow-up is 2 months. Of eight subjects (2 I, 6 A) evaluable for response at two months, three demonstrated a decrease in their tumor burden by 72% (I), 68% (A) and 52% (A), two subjects (2 A) exhibited stable disease and three subjects (1 I, 2 A) had disease progression. Six of the ten subjects (2 I, 4 A) demonstrated no Grade 3 or 4 adverse events. Grade 3 or 4 hematological adverse events (neutropenia, thrombocytopenia) occurred in four subjects including one febrile neutropenia and one of these four subjects also exhibited Grade 3 cellulitis. No tumor flare or tumor lysis has been observed to date. Conclusions: Preliminary data of lenalidomide monotherapy in relapsed and refractory NHL are encouraging.

[Table: see text]
RAD001 (everolimus) down-regulates cyclin D3 and c-Myc and is particularly effective in the treatment of aggressive B-cell lymphomas
Authors: Kuo S. H. , Hsu C. H. , Yeh P. Y. , Hsu H. C. , Gao M. , Cheng H. J. , Cheng A.
Published: March 2020

17573

Background: Aggressive B-cell lymphoma is recently found to be associated with constitutive activation of the PI3K/Akt pathway, and thereby is relatively resistant to apoptosis. Furthermore, activation of the PI3K/Akt signaling pathway can result in the upregulation of cyclin D3 and c-Myc through inhibition of the cap-independent RNA translation. Since mTOR is closely associated with the regulation of the translation process, and is a downstream mediator of the PI3K/Akt signalling pathway, this study aimed to examine if RAD001, an inhibitor of mTOR, can be effective in the treatment of aggressive B-cell lymphoma. Methods: Pfeiffer (diffuse large cell lymphoma), Ramos (EBV (−) Burkitt’s lymphoma), Raji (EBV (+) Burkitt’s lymphoma), and MC116 (EBV (−) undifferentiated lymphoma) cell lines were used in this study. Expression of pAkt, p70S6 kinase, pp70 S6 kinase, 4E-BP1, p4E-BP1, cyclin D3, and c-Myc was measured by immunoblotting. Results: Akt was constitutively activated in all four lymphoma cell lines. Downstream effectors of PI3/Akt signaling pathway, including p70S6 kinase and 4E-BP1, were also phosphorylated in these lymphoma cell lines. RAD001 downregulated p70S6 kinase and 4E-BP1, and the IC50s of growth suppression ranged from 5 to 50 nM, without significant difference between EBV (+) and EBV (−) cell lines. The IC50s of these lymphoma cell lines appeared to be much lower than those obtained from the carcinoma cell lines, suggesting that lymphomas may be particularly sensitive to growth inhibition by RAD001. RAD001 blocked cell cycle progression in G0/G1 phase in all four lymphoma cell lines while there was no significant increase in sub-G1 phases, suggesting that apoptosis was not the major mechanism of RAD001-induced growth inhibition. In addition, in parallel with the RAD001-induced growth inhibition, a dose-dependent down-regulation of the expression of cyclin D3 and c-Myc was demonstrated. Conclusions: The mechanism of action is at least partly due to downregulation of cyclin D3 and c-Myc, and subsequent G0/G1 block. Since overexpression of cyclin D3 and c-Myc is also closely associated with chemoresistance of aggressive B-cell lymphoma, RAD001 may be a useful adjunct in the treatment of this group of tumors.

No significant financial relationships to disclose.
The fears of men in a prostate cancer support group: A pilot study
Authors: Hausdorff J.
Published: March 2020

18616

Background: Little is published on prostate cancer patients’ fears and the effectiveness of interventional strategies. Methods: A 20-item questionnaire addressing various potential fears was administered to 30 men in a local prostate cancer support group: 15 had undergone curative therapy and were NED, and 15 had recurrent disease on androgen suppression. Level of fear for each question was rated from 1 to 5. At a later date, a different questionnaire was administered to 10 men with recurrent disease, addressing the predominant fear previously identified—uncontrolled symptoms at the end of life—with 10 specific questions on this subject. This was followed by the intervention: a 90 minute group discussion, led by an MD boarded in Medical Oncology and Hospice and Palliative Medicine. To assess impact, the 10 item questionnaire on end of life symptoms was readministered immediately after the discussion, and again 2 months later. Results: a) Patients with recurrent disease expressed a greater degree of fear than those free of recurrence; b) A major fear of the future is of uncontrollable symptoms at end of life, and was more of a concern than death itself; c) Of the 7 (of 10 total) items that were most significant to the patients (mean score 2.9 or higher, scale 1–5), a mean drop of 0.7 was seen in the level of fear following the intervention; d) This was inconsistently sustained 2 months later, with some concerns lessened but others not. Conclusions: In this small pilot study of men with prostate cancer, there appeared to be some measurable impact on the level of fear following the group discussion, though inconsistently sustained; questionnaires such as this are feasible to administer and appear to encourage productive discussion of difficult issues in the support group setting.

No significant financial relationships to disclose.
Bisphosphonates and oral cavity avascular bone necrosis: A review of 12 cases
Authors: Salesi N. , Pistilli R. , Marcelli V. , Govoni F. A. , Di Cocco B. , Pacetti U. , Di Fonso C. , Ciorra A. , Natali M. , Veltri E.
Published: March 2020

18628

Background: Intravenous bisphosphonates are the current standard of care for the treatment of hypercalcemia of malignancy and for the prevention of skeletal complications associated with bone metastases. Generally, the i.v. administration of bisphosphonates is well tolerated. Recently, retrospective case studies have reported an association between long-term bisphosphonate therapy and osteonecrosis of the jaws. Methods: We reviewed data for 12 patients referred to either an oral and maxillofacial surgeon or an oral medicine specialist for the management of clinically apparent chronic oral osteonecrosis of unknown etiology. All had received therapy cancer-related simultaneously with bisphosphonate management. Results: Typical presenting symptoms were pain and exposed bone at the site of a previous tooth extraction. In most patients, lesions initially occurred after dental extraction or other odontostomatological procedures, and 5 had a spontaneous event. Biopsy of the involved area showed the presence of necrotic lacunae, with infiltration of lymphocytes and histiocytes. In 9 cases, histological or cytological diagnosis of suspicious osteomyelitis was done. There was no observed correlation of the intraoral lesions with myelosuppression secondary to antineoplastic therapy. Conclusions: Based on these patients’ respective histories, clinical presentations, and responses to surgical and antibiotic treatments, it appears that the pathogenesis of this osteonecrotic process is most consistent with localized vascular insufficiency. In our opinion, the mechanism by which bisphosphonates could compromise bone vascularity may be related to its effect on the osteoclasts. The potent bisphosphonate mediated inhibition of osteoclast function serves to decrease bone resorption and inhibit normal bone turnover remodeling, resulting in microdamage accumulation and a reduction in some mechanical properties of bone.

No significant financial relationships to disclose.
Quality of life in children with osteosarcoma after limb salvage operation
Authors: Aono M. , Kudawara I. , Ohzono K. , Aoki Y. , Matsumine A. , Ieguchi M.
Published: March 2020

19501

Background: There are several options for the surgical management of osteosarcoma (OS) especially in the skeletally immature patients. We evaluate the clinical results and quality of life (QOL) of OS patients with limb salvage operations. Methods: From 1996 to 2005, ten children with newly diagnosed previously untreated nonmetastatic (stage IIB) OS of extremities were reviewed. There were 5 females and 5 males. The median age was 12 years (range, 8 to 14). Tumor locations: proximal humerus in 2, proximal femur in 1, distal femur in 2, proximal tibia in 3, distal tibia in 1, and tibial shaft in 1. Patients received neoadjuvant and adjuvant chemotherapy, and local wide resection of tumor. Limb salvage procedures: intraoperative extracorporeal autogenous irradiated bone graft (IORBG) in 4 and prosthetic replacement in 6. The functional results were measured for the patients accordance with the Musculoskeletal Tumor Society rating score. Results: With a median follow up of 4 years (range, 1 to 9), 7 were continuously disease free, 2 died of disease and in one there was no evidence of disease. No local recurrence was seen. Mean functional rating scores of patients with IORBG and prosthetic replacement were 82% (range 77 to 90) and 82% (range 57 to 93), respectively. Functional results were not different between these study groups and relatively good. There was one infection in patients with prosthetic replacement. There were subchondral collapse in 2 (50%), fracture in 1 (25%) and infection in 1 (25%) with IORBG. Conclusions: Limb salvage operation with neoadjuvant chemotherapy is the optimum treatment. However there remain several problems of function after limb salvage operations, with improvement of survival of pediatric osteosarcoma patient. We should select the most suitable surgical procedure to achieve the good function of limbs as well as local control.

No significant financial relationships to disclose.
Dramatic response of metastatic peripheral nerve sheath sarcoma to cetuximab combined with doxorubicin-based chemotherapy: Report of a case
Authors: Holmes J. P. , Reid T. J.
Published: March 2020

19503

Background: Soft tissue sarcomas are aggressive tumors that often show poor response to conventional chemotherapy agents. Some of these tumors over express epidermal growth factor receptor (EGFR) which is thought to promote tumor growth. Cetuximab, a monoclonal antibody to EGFR, is FDA approved for use in colon cancer. We report a case here of use in a patient with an aggressive soft tissue sarcoma. Case Report: A 32 yr male presented in April 2005 for routine follow up three months after completing adjuvant radiotherapy for retroperitoneal soft tissue sarcoma. At this time the patient was found to have recurrence of disease on routine surveillance scans. During workup of the recurrent masses, he developed acute bowel obstruction and went emergently to the OR. Multiple masses were removed and he was rendered grossly disease free. Adjuvant adriamycin and ifosfamide were planned; however, bulky masses were again noted on a pre-chemo staging study. After a single cycle of chemotherapy, he presented with abdominal pain, and an urgent CT scan ordered showed progressive disease. Immunohistochemical stains demonstrated strong expression of EGFR on his tumor. Cetuximab was added to his chemotherapy regimen. Repeat studies showed dramatic (>30%) decrease in his tumor burden after only two doses. As cycle three began, the patient developed acute abdominal pain and fever; emergent scans showed free air within the abdomen. The majority of his tumor burden had continued to decrease. The perforation could not be surgically managed and the patient was discharged to hospice. He expired ten days after discovery of the perforation. Conclusions: Addition of cetuximab to therapy for an aggressive soft tissue sarcoma which overexpressed EGFR resulted in dramatic decrease in tumor burden. Unfortunately, the patient suffered perforation of abdominal viscera and subsequently expired. Rapid tumor shrinkage likely contributed to the perforation. Use of cetuximab in patients with aggressive tumors expressing EGFR should be explored in the setting of clinical trials.

No significant financial relationships to disclose.
Prognostic significance of disseminated cancer cells in bone marrow in patients with squamous cell carcinoma of the esophagus using quantitative RT-PCR for CEA mRNA
Authors: Shinjo K. , Kajiyama Y. , Ishii Y. T. , Nagaoka I. , Tsurumaru M.
Published: March 2020

20004

Background: The clinical significance of disseminated cancer cells in bone marrow has not been elucidated in esophageal cancer. The aim of this study was to evaluate the relation between quantity of disseminated cancer cells in bone marrow and clinical characteristics, including prognostic significance, in patients with squamous cell carcinoma of the esophagus using real time reverse transcriptase polymerase chain reaction (RT-PCR) for CEA (carcinoembryonic antigens) mRNA. Methods: Bone marrow samples were obtained from the 4th or 5th right rib on thoracotomy from consecutive 65 operative patients with esophageal squamous cell cancer, who received esophagectomy with lymph node dissection. After total RNA extraction, they were investigated by quantitative real time RT-PCR for CEA. We also performed qualitative analyses to confirm the results at least twice. We adopted quantitative results when qualitative analyses showed positive. Results: In bone marrow CEA mRNA was detected in 14 out of the 65 patients (21.5%). There were no significant differences in clinicopathological findings between positive and negative group for bone marrow CEA. However, after a short median follow-up of 12 months (3–19 months), 6 of 14 (42.9%) patients with positive CEA group had been dead compared to 4 out of 51 (7.8%) patients with negative CEA group. The survival time of both group showed a significant difference (p=0.0282). However, there was no relationship between the amount of cancer cells in bone marrow and patients’ survival. Conclusions: Disseminated cancer cells in bone marrow using quantitative RT-PCR for CEA mRNA may be a significant predictor for highly malignant squamous cell carcinoma of the esophagus.

No significant financial relationships to disclose.
Identification of serum markers of glioblastoma multiforme patients using image-guided genomic and proteomic analysis
Authors: Guccione S. , Yang Y. , Chia Y. , Rubin D. , Wang Y. , Harsh G. , Atlas S. , Bednarski M.
Published: March 2020

20008

Background: Biomarkers in serum has been demonstrated to play a critical role in caner diagnostics. Glioblastoma multiforme (GBM) is a primary brain tumor with poor prognosis and low survival rate, which often has significant heterogeneity in morphology and increased vascular permeability and vessel density. In this study we identified molecules related to angiogenesis and vasculature development for GBM using a combination of contrast enhanced MR imaging, genomic and proteomic analysis, and enzyme immunoassay (ELISA). Methods: GBM patient without any prior procedures were scanned on a GE 1.5T MRI scanner using standard T1- and T2-weighted pulse sequences and gadopentetate dimeglumine as contrast agent. Samples from regions with contrast agent accumulation (contrast-enhancing, CE) and no uptake (non-enhancing, NE) were collected for microarray, Mass spectroscopic analysis and immunochemical staining. Patient serum samples were collected for protein expression quantification using ELISA assay. Results: Tissue samples from the CE and NE regions of 13 patients reveal significantly distinct gene expression patterns. Mass spectroscopy using MALDI system will also be examined. Growth factors such as laminin receptor, IGFBP-2, IGFBP-3, IGFBP-5, aFGF were all up-regulated in the CE regions, and immunohistochemical staining confirmed their protein expression. The presence of proteins with MW < 30 kD in the serum were examined using ELISA. IGFBP-2 showed to have a higher mean value (86.1 ± 29.1 ng/ml) in GBM serum as compared to healthy individuals (55.7 ± 9.9 ng/ml). Other potential markers such as IGFBP-3 and aFGF do not exhibit significant difference. Conclusions: CE-MRI using the clinical MRI agent Gd(DTPA) can reveal imaging features associated with increased vascular permeability and vessel density, and areas of fluid accumulation and necrosis. We have observed that differences in spatial resolution in the tumor correlate to changes in gene expression profiles, resulting in potential molecules that have high gene and protein expression levels in tumor area with high vascular activity and in serum. These targets can be used for diagnostic and clinical monitoring of the patient before and after therapeutic intervention.

No significant financial relationships to disclose.
CXCR4 is involved in multiple functions of cancer cells and is a compelling target for monoclonal antibody-based therapeutics
Authors: Boynton A. L.
Published: March 2020

20013

Background: CXCR4 is over-expressed on > 75% of cancers and absent on most non-neoplastic cells. It is a G protein coupled receptor spanning the cell membrane with CXCL-12 as its ligand. It is uniquely involved in 3 vital aspects of cancer: 1) proliferation; 2) motility; and 3) metastasis. Our objective was to assess specific Abs as candidates for clinical development in preclinical models. Methods: Several human cancer cell lines were used to study whether either mAbs specific to the CXCR4 receptor or to CXCL12 could inhibit: 1) proliferation; 2) chemotaxis; and 3) invasion through a reconstituted basement membrane. The ability of anti-CXCR4 Ab to inhibit tumor growth in vivo was also tested. Female Nod/Scid mice were injected IP with 2 × 105 human Namalwa tumor cells with 10 mice per group. Mice were injected with: Group 1) 100μg irrelevant IgG2b isotype control Ab; Group 2) 100μg CX02 anti-CXCR4 Ab; and Group 3) 100 μg CX05 anti-CXCR4 Ab. All mice in each group received an injection of Ab at day 2, 8, 14 and 20. Mice were observed for tumor growth over the following 4–5 months. Results: We originally found that CXCR4 was over expressed in fresh surgical human Glioblastoma, then showing that it was also over expressed in multiple cancer types. Specific anti-CXCR4 monoclonal Abs, CX02 and CX05 as well as anti-CXCL12 Abs demonstrated the ability to block cell proliferation of a variety of human Glioblastoma tumor cells including GB1690, HTB16, and 5GB, but not the proliferation of cells that do not express CXCR4. CX02 and CX05 Abs bind to live tumor cells with high affinity and have an EC50 of 3.2 and 2.7 μg/ml respectively (effective concentration required to provide 50% maximal median fluorescence shift). Both Abs (10 μg/ml) also inhibited by over 90% the motility of HS Sultan cells as demonstrated by the standard chemotaxis assays. In addition, both Abs (10–40 μg/ml) also inhibited the ability of HS Sultan cells to penetrate Matrigel, a reconstituted basement membrane assay used to assess malignant potential of cancer cells. Finally, both Abs were successful in extensively prolonging survival of Nod/Scid mice injected with human Namalwa cells. Conclusions: CXCR4 represents a compelling target for mAb therapy; Phase I clinical trails are pending.

[Table: see text]
Imatinib mesylate inhibits the growth of breast cancer cells mediated by PDGF-receptor-β and Akt inactivation
Authors: Mundhenke C. , Weigel M. , Meinhold-Heerlein I. , Schem C. , Bauerschlag D. O. , Jonat W. , Maass N.
Published: March 2020

20040

Background: The prognosis of patients with progressed breast cancer remains poor after intensive chemotherapy. Therefore new treatment options such as targeted therapies are needed. Imatinib Mesylate is a tyrosin kinase inhibitor targeting growth receptors like PDGF-R α and β, c-kit. These receptors and their downstream effectors trigger a cascade that regulates multiple cellular processes such as proliferation, differentiation and survival. The activity of the important downstream effector Akt leads to cell survival through inhibition of pro-apoptotic signals. We therefore evaluated the effects of Imatinib on of PDGFR β and Akt activity in breast cancer cell lines in vitro. We previously detected that Imatinib inhibits the growth of the breast cancer cell lines MDA MB 231, MCF 7, ZR 75–1 and T 47-D in vitro. Furthermore Imatinib induces apoptosis in these cell lines. Methods: To investigate effects on receptor activation, cells were stimulated with PDGF BB, the physiological ligand of PDGFR β. Phosphorylation of PDGFR β and Akt was examined after incubation with increasing concentrations of Imatinib by immunohistochemical and western blot assays. Imatinib concentrations from 2 μM to 10 μM were applied. Results: Imatinib Mesylate shows a dose dependent inhibitory effect on PDGFR β phosphorylation, determined by immunohistochemistry and western blot analysis. No changes in the expression pattern occured. The phosphorylation of the tyrosine kinase Akt can also be inhibited by Imatinib in a dose dependent manner. The expression of Akt remains also unchanged. Conclusions: It can be suggested that the growth inhibitory effect of Imatinib Mesylate on breast cancer cell lines is caused by a dose dependent decrease of activation in PDGFR β and Akt. The inhibition of Akt phosphorylation by Imatinib explains the induction of apoptosis. These interesting effects should be further validated in vivo in clinical trials.

[Table: see text]
Molecular identification, expression and prognostic role of estrogen alpha, beta and progesteron receptors in head and neck cancer
Authors: Timar professor J. , Lukits J. , Rásó E. , Kásler M. , Remenár É.
Published: March 2020

20056

Background: Previous data suggested hormone receptor protein expressions in head and neck cancer (HNC), but the molecular identification of the receptors was lacking and the prognostic significance was unclear. Methods: Sixty seven freshly frozen surgical samples of HNC patients were used throughout the study. Sex hormone receptor protein expression (ERa, Erb and PgR) of tumor cells was determined by immunocytochemistry. In case of positive reaction, data have been confirmed at mRNA level by nested-PCR and sequencing. Prognostic significance of the hormone receptor expression was determined by statistical analysis of the 4 year survival of the patients. Results: ER and PgR expressions confirmed by PCR analysis were frequent in HNC: 50.7 and 49.3%, respectively. Concerning the ER isoforms, ERa was predominant (41.8%) over ERb (28.4%) in both of oral as well as glottic cancers. The incidence of functional receptor expression (coexpression of ER and PgR) was relatively frequent in HNC: 41.8% which was independent of the anatomical location of the tumor. A minimum of 3 year follow up data were available for 51 HNC patients. Sex hormone receptor expressions did not affect survival, however, in the glottic cancer subgroup (n = 36) the ER expression was associated with a shortened 4 survival (23.1 versus 65.0%, respectively). Conclusions: ERa,b and PgR expression is frequent in HNC and may affect the prognosis of the disease at least in case of glottic cancer. On the other hand, the frequent coexpression of ER isoforms with PgR in HNC raises the possibility of clinical application of selective estrogen receptor modulators in this cancer type.This work is supported by the grant NKFP1a-0024–05.

No significant financial relationships to disclose.
Cancer risk of aged people with HIV infection and of transplant people
Authors: Serraino D. , Piselli P. , Busnach G. , Citterio F. , Fratino L. , Tirelli U. , Burra P. , Arbustini E. , Pradier C. , Giovanni R. , Carrieri P.
Published: March 2020

20063

Background: Acquired immunesuppression due to HIV-infection or to anti-rejection therapies following organ transplantation is a well known risk factor for cancer. This increased risk has been well documented for young adults, whereas few data are available on older persons. In this study, we assessed the impact of cancer in HIV-positive persons (HIV+) and in transplant persons (TRP) who were 50 years of age or older. Methods: Data from a multi-cohort study conducted in Italy and France were analysed. Individuals ≥50 years of age were selected from the original study group constituted by 2002 HIV+ seroconverters from Italy, 6072 HIV+ from France and 2755 Italian TRP (1844 kidney, 702 heart, 159 liver and 50 lung TRP). Sex- and age-standardized incidence ratios (SIR) and 95% confidence intervals (CI) were computed to quantify the cancer risk as compared to the general population. Among HIV+, the risk of cancer was also assessed according to treatment with highly active antiretroviral therapies (HAART). Results: This analysis was based on 94 cancers diagnosed in 833 HIV+, and on 154 cancers diagnosed in 1558 TRP ≥50 years of age. The SIRs for all cancers decreased with ageing, ranging from 5.1 (95% CI: 4.0–6.5) in HIV+ aged 50–59 to 2.1 (95% CI: 1.4–3.1) in HIV+ aged 60 or older. In TRP, the SIRs for all cancer were 2.5 (95% CI:2.0–3.1) and 1.6 (95% CI: 1.2–2.0), respectively. In HIV+, the protective effect of HAART was more evident in those aged 50–59 (SIR = 6.8 in never treated and SIR = 2.4 in ever treated) than in HIV+ aged ≥60 (SIR = 2.8 and SIR = 1.6, respectively). This pattern of cancer occurrence was peculiar to virus-related cancers (e.g., Kaposi’s sarcoma, non-Hodgkin’s lymphoma, liver cancer). SIRs for lung cancer in both groups were significantly increased but did not significantly differ according to HAART and/or age. The survival of both HIV+ and TRP was significantly reduced by the diagnosis of cancer, but the difference in survival was not associated with ageing (p = 0.20). Conclusions: Aged individuals with acquired immunesuppression have a cancer pattern similar to younger persons with immunosuppression, but the burden of cancer will increase in absolute terms because of the increasing proportion of older individuals among both HIV+ and TRP.

No significant financial relationships to disclose.
Gene expression analytics identify tissue of origin of unspecified metastatic cancers
Authors: Rigl T. , Buturovic L. , Pattin A. , Tran Q. , Nguyen L.
Published: March 2020

20082

Background: Identification of the tissue of origin for unspecified metastatic cancers is associated with improved outcomes. To aid in determining the origin of these cancers, we designed a semi-quantitative test that uses proprietary analytics and a companion genomic microarray to compare the expression signature of a biopsy specimen with those of the following types of cancers: bladder, breast, colorectal, gastroesophageal, germ line, hepatocellular, kidney, lung, lymphoma, melanoma, ovarian, pancreatic, prostate, soft tissue-sarcoma, and thyroid. More than 5,500 human specimens processed on Affymetrix HG U133A microarrays were analyzed to determine the test’s standardization algorithm. Methods: Studies across nine different laboratories were conducted to demonstrate the reproducibility required to support the potential clinical application of the test. Biopsy specimens of 604 metastatic cancers of known origin (by conventional pathological testing) were used to “train” the algorithm. An additional 636 samples then were tested. Diagnostic odds ratio (OR), sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR−) were determined for individual all-against-one tests. Results: Robust standardization, which involves 121 “house-keeping genes”, enabled the tissue of origin test to demonstrate reproducibility across nine different laboratories. Identification of the correct tissue of origin was associated with OR values ranging from 23 to >500, with averages for sensitivity of 83%, specificity of 99%, LR+ of 210, and LR− of 0.17. Conclusions: The PathWork Oncology Suite: Tissue of Origin (POS:TOO) test uses methods that are reproducible across laboratories. By analyzing microarray data with the POS:TOO algorithm, the test can identify the origin of metastatic tumors. Preparations for clinical validation studies are in progress and results will be submitted to FDA for clearance.

[Table: see text]
The clinicopathological and socioeconomic features of patients with gastric cancer in Turkey (Turkish Oncology Group)
Authors: Yalcin B. , Aydin F. , Zengin N. , Ilhan M. , Isikdogan A. , Aykan F. , Demir G. , Celik I. , Turhal S. , Icli F. , Akbulut H.
Published: March 2020

20098

Background: The incidence of gastric cancer has declined dramatically in western countries. However it is the second most common cancer in Turkey, and its mortality rate is still high. The aim of this study was to evaluate the clinicopathological and socioeconomic features of patients with gastric cancer in Turkey. Methods: A questionnaire including the clinicopathological and socioeconomic features of gastric cancer patients diagnosed in 2004, was used in this retrospective multicentre study. The characteristic of patients in economically developed Western Turkey (WT) was compared to those in less developed Eastern Turkey (ET). Results: From sixteen centers, 971 patients with gastric cancer during the year 2004 were included in the study. Male-female ratio was 2/1. Mean age was 57 ± 12.9 years. Of patients, 75.3% had low socioeconomic status. Distal and middle gastric cancers were the most common locations (distal 39%, middle 36.5% vs upper 24.5%). The R0 resectability rate was 54.1% in all patients. There was no statistically significant difference in gender, age, smoking rate, anemia, the location of tumor and the frequency of atrophic gastritis between WT and ET. The rate of cancer resectability was lower in Eastern Turkey (ET) than Western Turkey (WT) (31.6% vs. 63.4%, p = 0.0001). Also, socioeconomic status of patients was lower in ET than those in WT (53.6% vs. 32.3%, p = 0.0001). H. pylori associated gastritis and intestinal metaplasia were more common in ET when compared with WT (75.0% vs. 40.5%, P = 0.003, and 68.4% vs. 18.1%, respectively, P = 0.0001). Conclusions: Lower socioeconomic status and lower resectability rate of gastric cancer in ET is considerable. Further epidemiological study of gastric cancer is warranted in Turkey.

No significant financial relationships to disclose.
Promising targets in renal cell cancer: Met and ron-beta
Authors: Lambea J. J. , Alvarez I. , Lastra R. , Ortega M. , Aguirre E. , Ruiz-Echarri M. , Millastre E. , Mayordomo J. I. , Escudero P. , Storkus W. , Tres A.
Published: March 2020

20119

Background: The activation of Tyrosin Kinase Receptors (RTKs) produces several effects about cellular response. These are membrane receptors that bind differentiation signals, grow factors and cellular mediators. The interaction with their ligand causes the phosphorilation and internalization in the endosome. By a metabolic way, these receptors are degradated into the proteasome to small peptides that are expressed over the cellular surface joined to MHC class I mollecules, getting a better immunogenic recognition of the tumor cells. It is known that the bigger expression of the tyrosin kinase receptors in tumors is associated with an aggressive phenotype. For example overexpression of ephA2 or EGFR. Our study is based in the demostration of the overexpression of other receptors in renal cell cancer, a tumour with a disappointing response with treatment in advanced stages. On this way we can use them as targets for monoclonal antibodies and for citotoxic lymphocites CD8 stimulated that will join to peptides presented in MHC class I after the proteasomic degradation. Methods: We use Western-Blot for identifying the overexpressed RTKs in relation to normal tissue and as a reference the expression of beta-actin, that is present in every cells. The cells are from 5 murine renal cell cancer lines, (thanks to Hillman Cancer Center Institute, University of Pittsburgh. Pennsylvania. USA). The control is a murine cell line that is very similar to normal renal tissue (HK). We calculate the ratio of expression compared with the expression of normal tissue with an statistical analysis. Results: HER-2, VEGFR-2, Met, Ron-beta are overexpresed in renal cell cancer in a murine model, as EGFR (epidermic growing factor receptor). Conclusions: Met may be excellent therapeutic and inmunologic target and in selected cases of renal cell cancer. It’s known that EGFR and VEGFR are also good targets. Future research about these targets will get new options of combined immunotherapy (vaccines and monoclonal antibodies).

No significant financial relationships to disclose.
A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of the combination of an oral antimicrotubular agent, DJ-927 (D), and capecitabine (C) in patients (Pts) with advanced cancers
Authors: Beeram M. , Saif W. M. , Sarantopoulos J. , Schwartz G. , Patnaik A. , Tolcher A. W. , Mehdi F. , Feit K. , Takimoto C. H.
Published: March 2020

2016

Background: DJ-927, an oral microtubule stabilizer, has impressive cytotoxic activity in taxane-resistant tumors and an acceptable toxicity profile. C and Taxane combinations are active in solid tumors such as breast cancer. Non-overlapping mechanism of action and toxicity profiles and the convenience of an orally administered therapy have prompted a phase I evaluation of the combination. D was given orally once on day 1 and C for 14-days (D1–14), every three weeks. Methods: Eligible pts had evaluable cancer, minimal prior therapy and PS 0 - 2 ECOG. D was started at 18 mg/m2 on day 1 along with 1,250 mg/m2 of C orally B.I.D for 14 days, of a 21-day cycle. Incremental doses of both drugs were explored until the maximum tolerated dose (MTD) was reached. PK samples were collected during cycles 1 and 2, for assays of C and for D when given concurrently with C during cycle 1 and D given alone during cycle 2. Results: Twenty-seven pts [18 Male/ 9 Female; median age (range)- 58 yrs (33–70); PS 0 (n=8) ; PS 1 (n=19)] received 81 cycles [median (range)- 3 (1–8)] in 5 cohorts, with D and C 18/ 1250 mg/m2 (n = 3), 27/ 1250 mg/m2 (n = 7), 27/ 1900 mg/m2 (n = 7), 35/ 1900 mg/m2 (n = 3),and 27/ 2500 mg/m2 (n = 7). Dose-limiting toxicity (DLT) was grade 4 neutropenia in 2 of 3 pts at 35/ 1900 mg/m2 dose. Other common drug-related toxicities were leukopenia, nausea & vomiting (12 pts each, 44.4%), neutropenia, diarrhea and hand-foot syndrome (11 pts each, 40.7%), and fatigue (7 pts, 25.9%). A pt with hepatocellular carcinoma had an unconfirmed partial response at cycle 2 and 10 pts experienced disease stabilization lasting ≥ 12 weeks. The median elimination half-life (t½) of D was 182 hrs for cycle 1 (with C) and 204 hrs for cycle 2 (without C). Median tmax values for D with and without C occurred at 2 hours. Median clearance values (CL/F) for D in plasma were similar with and without C at 18.4 L/h/m2 and 19.8 L/h/m2, respectively. Conclusions: The combination of D and C is feasible and safe at the MTD of 27 mg/m2 and 2500 mg/m2, respectively. Co-administering C with D did not alter the PK of either drug. Preliminary evidence of antitumor activity suggests that further studies of this combination are warranted.

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Hand-foot syndrome (HFS) in patients receiving capecitabine: A pharmacological explanation
Authors: Ferrero J. M. , Lassalle S. , Mari M. , Formento J. L. , Francoual M. , Lacour J. P. , Etienne-Grimaldi M. C. , Hofman P. , Milano G.
Published: March 2020

2019

Background: Use of the oral fluoropyrimidine capecitabine, which generates 5FU in tumor tissues, is currently expanding. HFS is frequently associated with administration of capecitabine. However, the underlying pharmacological mechanism of HFS is still not elucidated. In a previous experimental study, we ruled out a possible implication of 5FU catabolites (FUH2 and FBAL) in the etiology of HFS (Anti-Cancer Drugs 15: 969, 2004). The aim of this study was to investigate expression levels of thymidine phosphorylase (TP, the main activating enzyme of capecitabine) and dihydropyrimidine dehydrogenase (DPD, the rate-limiting enzyme of 5FU catabolism) in skin samples from the palm area of the hand (target zone) and from the back (control zone). Methods: Paired-skin biopsies have been planned in 12 healthy volunteers, in agreement with the local ethical committee. Expressions of TP, DPD, and Ki67 (cell proliferation marker) were analyzed by a two-step immunohistochemical method using specific monoclonal antibodies (from Calbiochem for TP, Roche for DPD and Dako for Ki67) and immunoperoxydase revelation (kit ABC Vectastain). Results: Data from the first four subjects indicate no significant difference in the strong Ki67 staining between control and target zones. TP was markedly expressed in the basal layer of the epidermis (BLE), with similar staining in control and target zones. Interestingly, in 3 cases out of 4, DPD was strongly expressed (2+, 3+) in the BLE of the control zone and much less (0, 1+) in the paired-target zone. Definitive data on 12 subjects will be presented. Conclusions: This preliminary original observation suggests that capecitabine may be locally activated in the skin due to high TP expression. The relative absence of DPD expression in the palm area may explain the specificity of HFS, which may result from a lack of local 5FU catabolism. These new data open the way to a possible pharmacological approach to limit HFS.

No significant financial relationships to disclose.
Prognostic and predictive significance of 5-fluorouracil metabolic enzymes in colorectal cancer
Authors: Soong R. C. , Shah N. , Salto-Tellez M. , Han H. C. , Ng S. S. , Zeps N. , Joseph D. , Diasio R. B. , Iacopetta B. J.
Published: March 2020

2021

Background: Low levels of the 5-Fluorouracil (5-FU) metabolic enzymes, thymidylate synthase (TS), dihydropyrimdine dehydrogenase (DPD) and thymidine phosphorylase (TP) are linked to improved survival in colorectal cancer (CRC) patients receiving 5-FU chemotherapy. However, whether they are prognostic (related to tumor biology) or predictive (drug sensitivity) indicators is not clarified. This study aimed to (1) discriminate the prognostic and predictive significance of TS, DPD and TP and (2) ascertain the clinical and molecular subtype associations of the proteins in a large sample series. Methods: Tissue arrays containing sections from 956 stage 2/3 CRC cases were stained immunohistochemically for TS, DPD and TP. Associations with clinical and molecular characteristics and survival according to treatment status were assessed by Kruskall-Wallis and Kaplan-Meier analysis. Results: Low TS levels were associated with late stage, proximal tumor location and absence of microsatellite instability, low DPD with younger age and late stage and low TP with proximal tumor location. Low levels of all three enzymes associated with absence of tumor infiltrating lymphocytes. There were no associations with gender, grade or ras and p53 mutation. In stage 2 patients treated by surgery alone, those with low DPD levels had a worse survival than those with high levels (p<0.01). Stage 3 patients treated with chemotherapy had a better survival than those without in subgroups of patients with low TS (p=0.05), DPD (p<0.01) and TP (p=0.03) but not high levels of the proteins. Conclusions: Our results suggest the improved outcome of 5FU-treated patients with low tumor TS, DPD and TP levels may be due primarily to a benefit from adjuvant treatment rather than a favorable prognosis. TS, DPD and TP levels may be useful indicators for identifying CRC patients likely to benefit from 5-FU treatment.

No significant financial relationships to disclose.
Blood pressure (BP) as a biomarker for sorafenib (S), an inhibitor of the vascular endothelial growth factor (VEGF) signaling pathway
Authors: Maitland M. L. , Moshier K. , Imperial J. , Kasza K. E. , Karrison T. , Elliott W. , Undevia S. D. , Stadler W. , Desai A. A. , Ratain M. J.
Published: March 2020

2035

Background: Hypertension is a commonly reported toxicity of agents that inhibit the VEGF signaling pathway (VSP). This new class of cancer therapeutics has broad activity, but optimal dosing methods and integration into established treatment regimens could be enhanced by identification of reliable biomarkers. S, a new treatment for advanced renal cell carcinoma, is an orally available inhibitor of multiple VSP kinases including Raf-1 and VEGFR2. To characterize the chronicity and interindividual variability of BP responses to VSP inhibition we collected serial, standardized measures of BP and concurrent steady-state plasma concentrations ([plasma]) of S, from 30 patients (pts). Methods: Pts with advanced solid tumors, ECOG performance status < 2, and screening BP ≤ 140/90 mmHg on no more than one antihypertensive agent took 400mg S twice daily. Prior to therapy and at 3 time points after steady state [plasma] of drug was achieved, pts underwent 24-hour ambulatory BP monitoring with the SunTech Oscar PowerPack 2 (SunTech Medical, Morrisville, North Carolina). Readings were collected every 15 minutes during daytime hours and every 45 minutes overnight. Results: Unweigthed mean and standard deviations (sd) of systolic (SBP) and diastolic (DBP) 24-hr BP measurements were calculated for each pt. for the sessions pre-therapy and when steady state [plasma] S was reached (between days 6–10 after starting treatment). The differences in mean BPs between the two sessions were compared with (and p values reported for) paired t-tests. Regression analysis of [plasma] of S with either DBP or SBP, or change in DBP or SBP, with main effect and interaction terms for albumin, age, and sex revealed no significant correlation between S [plasma] and BP response. Conclusions: BP elevation is a biomarker for VSP inhibition. The known variability (coefficient of variation = 70%) in total S steady state plasma concentrations did not account for the observed variability in BP response.

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Pharmacokinetic (pk) and safety study of irinotecan (Ir) and capecitabine (Cp) administered on a weekly schedule
Authors: Gollamudi R. , Baker S. D. , Desai K. K. , Chaudhary I. , Kaubisch A. , Camacho F. J. , Einstein M. , Goldberg G. , Goel S. , Mani S.
Published: March 2020

2061

Background: In vitro studies show synergy between Cp and Ir. Since both drugs are metabolized by carboxyl esterases (CE), the potential for competitive inhibition is possible. We conducted a study to identify a safe dose and potential drug-drug interactions of this combination. Methods: This was an open-label phase I dose escalation trial. Ir was given as a 30 min infusion on days 1 and 8, and Cp on days 1–14 of a 21 day cycle. Plasma for pk analyses was drawn on days 1 and 8, at 0, 15, 30, 45, 60, 90, 120, 240, 360 min, and 24 hr, for total CPT-11, SN-38, SN-38-glucuronide (G), and APC. Results: 47 patients (pt) - median age 60 (32–83) years; performance status 0–1 (96%); diagnoses- ovarian (10), breast (5), cervical (5), colorectal (10) and others (17) received 202 (median 4, range 1–18) cycles in 6 dose cohorts - Ir (mg/m2)/Cp (mg/m2/day in 2 divided doses) 75/1500, 85/1500, 85/1750, 100/1750, 100/2000, 115/2000. At the highest dose tested (115/2000), 1 of 3 pt developed grade (G) 4 neutropenia with fatal gram-negative sepsis. At dose level 5 (100/2000), 2 of 21 patients developed cycle 1 DLT - G 3 diarrhea/vomiting and G 3 diarrhea. Across all doses and patients, the G 3–4 toxicities observed were diarrhea (12 pt), vomiting (2 pt), fatigue (5 pt), hand-foot syndrome (1 pt), neutropenia (6 pt), anemia (4 pt), thrombocytopenia (2 pt) and elevation of AST/ALT (1 pt). Anti-tumor responses include partial response in 8 of 35 evaluable (23%) pts (3 breast, 4 ovarian, 1 cervical), a minimal response (1 breast), and a 90% decline in PSA (1 pt). Detailed pk analyses show that AUC(0-∞) of Ir, SN-38G, and APC were similar on days 1 and 8. However, SN-38 Tmax was longer on Day 8 (0.87 hr vs. 1.22 hr, p = 0.012). While SN-38 AUC (0-∞) was higher on day 1 by 45%, this was not statistically significant (p = 0.167). Conclusions: Cp results in a delayed conversion of Ir to SN-38, suggesting competitive inhibition of CE at a molecular level without clinical significance. This could portend a drug-drug interaction when Ir is combined with substrates of CE, and warrants further study. The combination of Ir and Cp is safe and well tolerated at 100/2000, and warrants further evaluation in breast, cervical, ovarian and other malignancies.

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Results of phase I clinical trials of Coramsine in patients with advanced solid tumors
Authors: Millward M. , Powell A. , Daly P. , Tyson S. , Ferguson R. , Carter S.
Published: March 2020

2070

Background: Coramsine (C) is a 1:1 mixture of solasonine and solamargine, plant glycoalkaloids found in the species Solanum Linneanum, with single agent and synergistic combination in vitro and in vivo preclinical efficacy in various tumor models through interaction with rhamnose-containing cell membrane glycoproteins and subsequent internalization. Methods: C initially as a 2-hr IV infusion daily × 5 every 2 weeks to define the MTD, recommended Phase II dose, toxicity and pharmacokinetics. Based on preclinical toxicology the infusion duration was increased to 4 hours and 24 hours (120 hr continuous infusion). Doses studied range from 0.75 mg/kg/day to 3.0 mg/kg/day. Results: 27 pts were treated. DLT occurred in 2/2 pts at 1.5 mg/kg/day (2 hr) and 2/2 pts each at 3.0 mg/kg/day (4 hr and 24 hr). Preceding dose levels 1.0 mg/kg (2 hr) and 1.5 mg/kg (4 hr) produced DLT in 2/6 pts each with no grade IV. Over 24 hr, 2.25 mg/kg/day produced DLT in 4/6 patients. Limiting toxicity at all schedules was grade III/IV transaminitis with grade I-III increases of bilirubin and grade I-II creatinine. Hepatotoxicity was maximal at days 3–5, resolved over 10–21 days, was clinically asymptomatic apart from grade I-II fatigue, and was not cumulative. No myelosuppression or other serious drug-related toxicity was recorded. Partial responses were documented in 2 pts (renal, NSCLC) and minor response in 1 pt with unknown primary. Responses were seen using both 2 hr and 4 hr infusions. Pharmacokinetic parameters for solasonine and solamargine are linear across the narrow range of doses studied with elimination T1/2 of 5.57 ± 1.27 hr (solasonine), 8.40 ± 2.00 hr (solamargine) and Cl of 5.6 ± 1.6 L/hr (solasonine), 3.0 ± 0.7 L/hr (solamargine). Peak levels of both exceed active in vitro levels (>2,000 ng/ml). Conclusions: Coramsine produces dose-limiting hepatotoxicity at doses above 1.0 mg/kg/day over 2 hours or 1.5 mg/kg/day over 4 hours. 2.25 mg/kg/day over 24 hours exceeds the MTD. Activity has been seen against resistant solid tumors. Phase II studies in renal cancer and melanoma will be performed using 1.5 mg/kg/day over 4 hours.

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