bluuebunny/crossref_metadata_2025 huggingface dataset:
CD8 count measurement has independent prognostic significance in individuals with AIDS-Kaposi sarcoma
Authors: Stebbing J. , Sanitt A. , Teague A. , Powles T. , Nelson M. , Gazzard B. , Bower M.
Published: March 2020

20500

Background: We recently published a prognostic index for Acquired Immunodeficiency Syndrome (AIDS)-associated Kaposi sarcoma (KS) diagnosed in the era of highly active antiretroviral therapy (HAART) based on clinical and routine laboratory characteristics. Because immune subset measurement is often performed in human immunodeficiency virus (HIV) positive individuals, we examined whether these were predictive of mortality independently of the prognostic index, or could predict time to progression of KS. Methods: We performed univariate and multivariate Cox regression analyses on a dataset of 326 individuals with AIDS-KS to identify immune subset covariates predictive of overall survival and time to progression. Adaptive (CD8 T cell and CD19 B cell) and innate (CD16/56 natural killer cell) immune parameters were studied by flow cytometry. Results: In univariate analyses all 3 immune subsets had significant effects on overall survival (p < 0.025). In multivariate analyses including the prognostic index, only CD8 counts remained significant (p = 0.026) although its effect on the overall prognostic index is small. An increase of 100 cells/mm3 in the CD8 count confers a 5% improvement in overall survival. Individuals with a higher CD8 count did not have an increased time to progression. Patients who were already on HAART at the time of KS diagnosis did not have a shorter time to progression than those who were antiretroviral naïve at KS diagnosis. Conclusions: The CD8 count appears to provide independent prognostic information in individuals with AIDS-KS. Measurement of the CD8 count is clinically useful in patients with KS.

No significant financial relationships to disclose.
International collaboration is feasible in trials for rare conditions: The EURAMOS experience
Authors: Marina N. , Bielack S. , Sydes M. , Bernstein M. , Butterfass-Bahloul T. , Smeland S. , Holiday A. , Whelan J.
Published: March 2020

20501

Background: Osteosarcoma is rare and the outcome for patients has plateaued following the introduction of multi-agent chemotherapy. To demonstrate further improvements would likely require large numbers of patients, only achievable in this setting via International collaboration. Therefore, in October 2001, 4 multinational groups - Children's Oncology Group (COG), Cooperative Osteosarcoma Study Group (COSS), European Osteosarcoma Intergroup (EOI) and Scandinavian Sarcoma Group (SSG) - agreed on the merits of collaboration to determine whether altering post-operative therapy based on histological response improved outcome. Following a number of practical and regulatory hurdles the trial opened to accrual in April 2005. Methods: Eligibility criteria include: new diagnosis with resectable osteosarcoma; age <40 years; normal organ function. Standard therapy includes 29 weeks of cisplatin, doxorubicin and high-dose methotrexate (MAP). Following two cycles of cisplatin/doxorubicin and 2–6 cycles of high-dose methotrexate, patients undergo resection. Post-operative therapy is dependent on histological response. Good histological responders (>90% necrosis) are randomized to continuing MAP or MAP with maintenance pegylated interferon. Poor histological responders are randomized to MAP or MAP plus ifosfamide and etoposide. Results: All groups are recruiting and accrual is ahead of schedule: 373 patients have been enrolled (159 COG, 108 COSS, 83 EOI, 23 SSG) and 160 patients randomized: 87 (54%) good responders (46 MAP), 73 (46%) poor responders (39 MAP). Conclusions: International collaboration is feasible and results in rapid accrual of large number of patients. The implementation of such trials is difficult and time consuming due to the complexity of multinational regulatory issues. However, the effort is worthwhile to potentially improve outcomes for patients with rare diseases.

No significant financial relationships to disclose.
Clinical, pathological and immunistochemistry characterization of primary breast cancer metastasizing to the central nervous system (CNS): Analysis of time to development of CNS metastasis
Authors: Filho A. F. Ferreira , Saueressig S. , da Silva D. L. , dos Santos M. P. , Wunder A. P. , Santana R. , Zetler C.
Published: March 2020

2051

Background: The characterization of breast cancer patients (BCP) with high risk of developing CNS metastases still remains a challenge. The identification of these patients could enable new strategies of prevention, early detection and innovative treatments. Methods: We analyzed the records of 950 BCP treated at our institutions during 1997 to 2003 and found that 38 (4%) of these patients developed CNS metastases. In these 38 patients, we reviewed the clinical course, initial pathology and the primary tumor immunohistochemistry profile of hormone receptors, HER-2, p53, as well as microvessel density by the Chalkey count technique by the anti-CD105 antibody E-9. Results: Median age was 54 years (30–75), 11% < 40 years, median tumor size was 3.5 cm (1.2–17). Median number of positive axillary nodes was 6 (0–27) and axillary lymph nodes were negative in 10 patients (29%). Only two patients (5%) had grade 1 tumors. The median survival after the development of CNS metastases was of 4.5 months (0.5 - 27 months), with 8% of patients living longer than one year. Treatment consisted of whole brain radiotherapy in 79% of the patients. Hormone negative receptor status was found in 24 patients (63%), HER-2 was overexpressed in 26 patients (68%) and p53 was positive in 16 patients (46%). Mean Microvessel density was > 7 in 23 patients (59%). For the whole group of patients, the median time to the development of CNS metastases was 22 months (5–96). Patients with p53 positive tumors had a lower time to development of CNS metastasis (19.3 versus 34.6 months, p = 0.005), as compared to p53 negative tumors. No differences were found between subgroups of patients, as defined by tumor grade, microvessel density, hormone receptors and HER-2 status, or positivity of axyllary lymph nodes. Conclusions: The primary tumors of BCP who developed CNS metastases showed a high percentage of hormonoreceptor negativity (63%), overexpression of HER-2 (68%), and high counts of microvessel density . While the role of CD 105 expression and the development of CNS metastases in BC patients deserve further research, p53 positivity may be a marker of risk of early development of CNS metastases in BCP.

No significant financial relationships to disclose.
Synovial sarcoma: Retrospective analysis of treatment outcome and prognostic factors
Authors: Memon M. A. , Allam A. A. , El-Enbaby A. M. , El-Sebaie M. , Khafaga Y. M. , Schultz H. , El-Weshi A.
Published: March 2020

20517

Introduction and Objectives: Synovial Sarcoma (SS) account for approximately 10 % of soft tissue sarcoma. Despite numerous case reports and several relatively large series, debate still exists about the prognostic factors for this disease, the biologic behavior and role of adjuvant chemotherapy. The purpose of this study is to analyze the variable prognostic factors that may affect the treatment outcome in patients with SS. Patient and Methods: Sixty-six patients with SS (36 males and 30 females) were seen in institution between January 1985 and December 2000. Median age at diagnosis was 29 years. Site of involvement include, lower extremities 43/66 cases; (65%), upper extremity 16/66 (24%), trunk 3/66 (5%), others 4/66 (include larynx, thyroid, neck, and hypopharynx).Tumor size: = 10 cm 42/66 (64%), = 10 cm 24/66 (36%). Patients with stage III and IV disease represented 58% of all patients (38/66), stage I and II 42%(28/66). All patients underwent surgery and adequate resection margins(= 2 cm) were achieved in 52% of cases. Histopathology: Biphasic 36/66, Monophasic 16/66, spindle cell 12/66 and not otherwise specified 2/66. Radiation therapy was given 44/66 cases (67%). Chemotherapy was delivered to 11/66 patients (17%). Results: With a median follow up of 50 months, the 5-year overall survival (OS) for all patients was 45%, while the 5- year relapse free survival (RFS) for patients treated with radical intent was 32%. Prognostic factors that significantly affected OS on univariate analysis were tumor size (≤ 10 cm vs > 10cm), tumor stage (stages I and II vs stage III), adequacy of surgical resection and local control. On multivariate analysis, tumor size and local control were the only independent factors that did affect OS. For RFS, sex, tumor size, tumor grade, tumor stage, and adequacy of surgical resection were the prognostic factors of significance on univariate. Tumor stage and sex were the only independent prognostic factors of significance on multivariate analysis for RFS. Conclusion: Tumor size, stage, grade, and adequacy of surgical resection are the main prognostic factors affecting OS and RFS. These parameters can help to identify the high risk patient who may qualify for aggressive treatment.

No significant financial relationships to disclose.
The utility of the MDASI-BT in assessing symptoms in patients with brain metastases
Authors: Armstrong T. S. , Mendoza T. , Gning I. , Smith M. L. , Gilbert M. R. , Weinberg J. , Cleeland C.
Published: March 2020

2052

Background: Symptom occurrence has been shown to predict treatment course and survival in patients with solid tumors. The M. D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) was recently validated in patients with primary brain. This study evaluated the reliability and validity of the MDASI-BT as well as symptom severity and prevalence in patients with brain metastases. Methods: Patients diagnosed with systemic cancer with brain metastases participated in this cross-sectional study. Data collection included demographic and clinical factors, and the MDASI-BT (0–10 scale). The average for the 22 symptoms and 6 interference items scores the MDASI-BT was computed. Construct validity was assessed using confirmatory factor analysis, and known-group validity was evaluated by detecting group differences due to disease severity and performance status. For reliability, Cronbach’s alpha values were computed for each subscale. Results: A sample of 124 patients participated, of which 53.2% females. Participants were primarily white (79.8%) and married (78.2%), with a variety of solid tumor malignancies represented. Factor analysis revealed six underlying constructs including affective, cognitive, focal neurologic deficit, constitutional, gastrointestinal, and interference with life. This solution explained 68.4% of the variance, and satisfied Harman’s criteria for model fit. Known-group validity was established for the MDASI-BT using the Karnofsky performance status (KPS). Mean symptom scores were 1.2 and 2.6, and mean interference were 1.8 and 4.3, for patients with good (90–100) and poor KPS (80 and below) respectively (p<0.001). These subscales were also sensitive to opioid analgesic use with group differences of 1.5 and 2.2 (p<0.001). Cronbach’s alpha was 0.9 for each of the two subscales. Fatigue, sleep disturbance, drowsiness, distress, and dry mouth were the most severe symptoms. Conclusions: The MDASI-BT demonstrated validity and reliability in patients with brain metastases and can be used to identify symptom occurrence related to the tumor and therapies.

No significant financial relationships to disclose.
Gemcitabine in heavily pretreated adult soft tissue sarcoma patients
Authors: Schoeler D. , Kunitz A. , Reichardt P.
Published: March 2020

20524

Background: The number of effective cytotoxic agents in treatment of advanced soft tissue sarcoma (STS) is limited when patients have failed anthracyclin and ifosfamide therapy. There are inconsistent data in phase I / II studies and retrospective analyses evaluating the efficiacy of gemcitabine (G, 900mg/m2, d1+8, q3w) or combination of gemcitabine and docetaxel (GD, G: 900mg/m2, d1+8, D: 100 mg/m2, d8, q3w). Methods: Between 2002 and 2006 we retrospectively analyzed 14 females and 6 males with heavily pretreated advanced soft tissue sarcoma (1–5 pretreatments) who were treated in our department (Charité Campus Virchow-Klinikum) with G (n=10) or GD (n=10) depending on their performance status. The following histology types were represented: leiomyosarcoma (10), liposarcoma (3), MPNST (3), synovial sarcoma (2), undifferentiated sarcoma (1), malignant large cell sarcoma (1). Results: A total of 99 cycles (range 1 to 15) were applied. Best response was partial remission (PR=20%, G: n=2, GD: n=2) and was achieved in four patients, among them three leiomyosarcoma and one MPNST. In six cases disease stabilization was achieved for up to 15 month (SD=30%, G: n=2, GD: n=4). Four patients had progressive disease after 2–3 cycles of gemcitabine based therapy (PD=20%, G: n=0, GD: n=4). In another six cases only day one of the first cycle (G alone) was administered because of serious problems due to pretreatment and poor performance status (e.g. prolonged thrombopenia and neutropenia Grade IV, gemcitabine-induced vasculitis, gastrointestinal bleeding due to tumor localization, pneumonia, rapid tumor progression). Conclusions: Gemcitabine-based therapy for heavily pretreated STS patients in our retrospective analysis has a significant overall response rate. In patients considered unfit for GD combination, single agent G treatment remains an option with moderate effiacy.

No significant financial relationships to disclose.
Treatment of adult rhabdomyosarcoma
Authors: Staddon A. P. , King J. J. , Ogilvie C. M. , Hartner L. , Fox E. J. , Lackman R. D.
Published: March 2020

20526

Background: Adult rhabdomyosarcomas are rare tumors that are clinically aggressive with high rates of metastasis. This study aimed to determine short-term patient outcomes and responses to chemotherapy using doxorubicin, ifosfamide, and vincristine in the treatment of adult rhabdomyosarcomas. Methods: After IRB approval, 13 adult rhabdomyosarcoma patients (8 males, 5 females) were identified from 1998 until 2006. Of these patients, 6 had metastatic disease on presentation, 4 had neoadjuvant treatment, and 3 had adjuvant treatment. One patient with metastatic disease refused treatment. Twelve patients were treated with doxorubicin, ifosfamide, and vincristine initially with 2 patients also receiving cyclophosphamide and VP-16. The standard regimen was doxorubicin 25 mg/m2 D1- 3, ifosfamide 2.5 gm/m2 D1–4, and vincristine 1.4 mg/m2 D1,8 every 21 days. The majority of patients received 6 cycles of chemotherapy. Average age was 48 years (20 to 73 years). Seven had pleomorphic subtype, 3 alveolar, and 2 embryonal. The primary tumor was in the upper extremity in 4 patients, lower extremity in 5, chest wall in 2, and cervix in 1. Outcome measures were response to chemotherapy, disease status at last follow-up, and survival from the initiation of treatment. Results: Of the 5 treated patients with metastatic disease on presentation, 1 had a complete response (CR) and has no evidence of disease (NED) post-resection at 14 months. 1 had progression and is alive with metastasis at 5 months. 3 patients had a partial response (PR) with later progression and died of disease at 8, 14, and 24 months. Of the 4 patients treated neoadjuvantly, 3 are currently alive NED at 7, 10, and 10 months (2 had pathologic CR and 1 had PR) and 1 patient had a PR with later progression and died at 19 months. Of the 3 patients treated with adjuvant chemotherapy, all 3 are alive NED at 2, 17, and 37 months. Median overall survival was 12 months with 8/12 (67%) alive at last follow-up and 7/12 (58%) alive NED at a median of 10 months. Conclusions: Treatment of adult rhabdomyosarcoma using doxorubucin, ifosfamide, and vincristine shows significant activity with some pathologic CRs and a 58% disease-free survival rate at a median of 10 months.

No significant financial relationships to disclose.
Does neo-adjuvant chemotherapy increase the risk of infection after limb salvage surgery for bone tumors?
Authors: Sankaranarayanan S. , Sokolovskiy V. , Voloshin V. , Aliev M. , Zubikov V. , Nisichenko D. , Sokolovskiy A.
Published: March 2020

20532

Background: Neo-adjuvant chemotherapy is commonly used to eradicate the micro metastases and to prepare the patient for limb-salvage surgery. It helps the surgeon to get good oncological margin intraoperatively. Methods: Between the period of 1992 - 2005, 321 patients underwent limb salvage surgery for bone tumors at the Department of General Oncology (Bone & Soft tissue tumors), N. N. Blokhin Russian Cancer Research Center & Moscow Regional Clinical Research Institute, Moscow, Russian Federation. 230/321 patients (Group A) received neo-adjuvant chemotherapy. The course of chemotherapy ranges from 2 to 11 cycles. 95/321 patients (Group B) did not receive neo-adjuvant chemotherapy. The histological diagnoses were: 155 - High grade osteosarcoma, 38 - Giant cell tumor, 36 - Malignant fibrous histiocytoma, 29 - Chondrosarcoma, 25 - Periosteal osteosarcoma, 21 - Metastasis from other organs and 17 - Ewing's tumor. Results: In Group A, 27 patients (11.7%) and in Group B, 7 (7.3%) had infection of endoprosthetic bed. Suppression of the immune system by chemotherapeutic agents is the main reason for the higher incidence of infection in Group A. All the 27 patients in Group A and 2 patients in Group B had revisional endoprosthetic replacement. In group A 7/27 and in Group B none of the 7 patients died of post operative infection. The follow-up ranged from 1 - 13 years (mean follow-up 6 years). Discussion: In our opinion, it has a major disadvantage, i.e. it increases the risk of postoperative infection. How best to combine this drug is still unknown. In the future, therapy for bone tumors should be enhanced by advances in pharmacology, immunology, and molecular genetics that will lead to more efficacious, specific and less toxic treatments. An interdisciplinary team approach is needed in order to advance the goal of local tumor control, limb salvage with optimum extremity function, minimal morbidity and improved long term survival.

No significant financial relationships to disclose.
A case report of sarcoma regression in a patient with MDS treated with lenalidomide
Authors: Shammo J. M. , Kassar M. , Robin I. , Knight R.
Published: March 2020

20535

Background: Lenalidomide is an immunomodulatory drug recently approved for the treatment of MDS patients with del 5q cytogenetic abnormality. Here we describe a case of sarcoma regression in a patient with MDS who had been treated with lenalidomide. Method: An 84 year old man was diagnosed with low risk MDS in November 2002, he was transfusion dependent requiring 2–4 units of blood a month. He was enrolled on the MDS 002 trial in February 2004. He became transfusion independent by cycle 4. Results: In March 2005 he developed abdominal pain and a CT of the abdomen revealed a 2 x 2 cm mass involving the lesser curvature of the stomach. An MRI of the abdomen followed, confirming the presence of an enhancing gastric lesion, a biopsy of the mass revealed low grade malignant sarcoma. The patient was a poor surgical candidate and the decision was made to follow the progression of the mass with repeat imaging. In October 2005 a repeat MRI failed to visualize the previously noted mass, a recent CT performed in December 2006 was also negative for the presence of the mass. A potential therapeutic role for lenalidomide in this case which may have led to the regression of the sarcoma is possible although spontaneous regression can not be ruled out. It is not known if the mass was present at the time of enrollment on the clinic trial, it is also not clear as to why the patient presented with abdominal pain several months into the clinical trial. There had been several case reports in the literature describing similar results with thalidomide in patients with soft tissue sarcoma however, to our knowledge this clinical observation has never been reported with lenalidomide previously. Conclusion: This observation merits consideration for prospectively evaluating the efficacy of lenalidomide in patients with sarcoma for whom limited therapeutic options currently exist.

No significant financial relationships to disclose.
Phase I study of erlotinib and CCI-779 (temsirolimus) for patients with recurrent malignant gliomas (MG) (NABTC 04–02)
Authors: Robins H. I. , Wen P. Y. , Chang S. M. , Kuhn J. , Lamborn K. , Cloughesy T. , Glibert M. R. , Yung W. K. , Dancey J. , Prados M. D.
Published: March 2020

2057

Background: Glioblastomas (GBM) frequently have amplification/mutation of EGFR and inactivation of PTEN. Although single agent EGFR and mTOR inhibitors have only modest activity, there is a rationale for combinations of these agents. Methods: The North American Brain Tumor Consortium (NABTC) is conducting a phase I/II study of the EGFR inhibitor erlotinib in combination with the mTOR inhibitor CCI-779 in recurrent MG. Eligibility criteria were histologically proven GBM and anaplastic gliomas (AG), radiologic progression, > 18 yrs old, KPS > 60, adequate bone marrow reserve and organ function. Patients (pts) must not be receiving enzyme inducing antiepileptic drugs. The dose of erlotinib was fixed at 150 mg/d. Patients initially received CCI-779 50 mg intravenously once weekly and the dose was adjusted based on toxicities. Dose-limiting toxicities (DLT), determined during the first 4 weeks of therapy, were defined as any grade (G) 4 hematologic toxicity except for G3 thrombocytopenia, and any G3 or unacceptable G2 non-hematologic toxicities. Escalation was performed in groups of 3. The maximum tolerated dose (MTD) was defined as the dose at which DLTs occurred in no more than 1/6 pts. Results: To date 22 eligible pts have been enrolled (15 GBM; 7 AG). Patient characteristics were 12 male, 10 female; median age: 54 (26–74); median KPS 90 (70–100); median prior chemotherapy regimens 1 (0–3). Two of 3 pts receiving 50 mg of CCI-779 developed DLTs (intolerable G2 rash & mucositis, & G3 liver function abnormalities; G3 rash & dehydration). Three of 6 pts receiving 25 mg of CCI-779 weekly experienced DLTs (G3 rash; G3 rash, diarrhea, dehydration; G3 mucositis & infection). Two of 6 patients receiving weekly 15 mg of CCI-779 experienced G3 rash. The protocol was amended to define a DLT only if > G3 toxicities persisted despite maximal therapy. Six additional pts were treated at 15 mg of CCI-779. One of 6 pts developed a G3 rash. Conclusions: The combination of erlotinib and CCI-779 was associated with a higher than expected incidence of rash and mucositis. The MTD for this combination is likely to be 150 mg/d of erlotinib and 15 mg/d of CCI-779. Final pharmacokinetics and response data will be presented.

No significant financial relationships to disclose.
A phase I trial of sorafenib (BAY 43–9006) for patients with recurrent or progressive malignant glioma (NABTT 0401)
Authors: Nabors L. B. , Rosenfeld M. , Chamberlain M. , Phuphanich S. , Batchelor T. , Supko J. , Desideri S. , Xiaobu Y. , Wright J. , Grossman S.
Published: March 2020

2058

Background: Sorafenib (BAY 43–9006) is a small molecule inhibitor of multiple kinases to include raf, VEGF receptors, and PDGF receptors. The molecule has demonstrated anti-proliferative and anti-angiogenic activity in a number of in vitro and in vivo model systems. Methods: In this multi-institutional trial, we have conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Cohorts of 3 patients, stratified based on the use of enzyme inducing anticonvulsants (EIAC) or not (non-EIAC), have completed enrollment through the following dose levels: 200 mg, 400 mg, 600 mg, and 800 mg. Therapy has been given as a twice daily oral administration with cycles of 28 day duration. Results: A total of 35 patients have been enrolled and are evaluable for toxicity. Treatment related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematological toxicity, and grade 4 hematological toxicity (platlets and ANC) or febrile neutropenia of any duration. The following DLTs were observed: one grade 3 hand-foot-syndrome at the 400 mg BID (EIAC), one grade 3 puritis 400 mg BID (non-EIAC) dose level, grade 3 hand/foot syndrome 800 mg BID (EIAC and non-EIAC arms), grade 3 hypophosphatemia 800 mg BID (EIAC), and grade 3 joint pain 800 mg BID (EIAC). A MTD of 600 mg BID has been defined for the EIAC arm with 3/6 DLTs at 800 mg BID. A MTD has not been defined and enrollment has been completed through the 800 mg BID dose level for the non-EIAC. Of the enrolled patients, 20 are with glioblastoma multiforme (GBM), 8 with anaplastic astrocytoma (AA), and 7 with anaplastic oligodendroglioma (AO). Conclusions: The MTD for sorafenib is 600 mg BID for patients on EIAC. Sorafenib is well tolerated with limited toxicities to doses of 800 mg twice daily in patients with recurrent malignant glioma not on EIAC (non-EIAC arm).

No significant financial relationships to disclose.
A phase I trial using the proteasome inhibitor bortezomib and concurrent temazolomide and radiotherapy for high grade gliomas
Authors: Dicker A. , Werner-Wasik M. , Machtay M. , Mallon G. , Ramirez M. , Andrews D. , Curran W. J.
Published: March 2020

2061

Background: Improving the response of patients with high-grade astrocytomas continues to remain a challenge despite advances in chemoradiation. Preclinical studies have demonstrated the importance of the NF-kappaB pathway treatment resistance and enhancement of radiosensitivity by proteasome inhibition. This open-label, phase I study evaluated the safety of 3 dose levels (0.7, 1.0, 1.3 mg/m2/dose) of intravenously administered bortezomib, a reversible proteasome inhibitor with unique properties in combination with chemoradiation. Methods: Eligible patients had a diagnosis of high-grade glioma. Other requirements included performance status 0–1 and adequate hematologic reserve. Previous radiotherapy and/or chemotherapy was allowed. Patients received fraction sizes of XRT that ranged from 1.8–3.5 Gy/day for total doses between 35–66 Gy. During radiotherapy, temozolomide was administered continuously at a daily dose of 75 mg/m2. The starting dose level of bortezomib was 0.7 mg/m2/ days 1, 4, 8, 11 of 21-day cycle for up to 2 cycles. This was followed by 1.0 mg/m2 and 1.3 mg/m2 dose levels. The primary endpoint of the study was dose-limiting toxicity (DLT), defined as any Grade 4–5 toxicity or Grade 3 toxicity(ies) requiring hospitalization and/or XRT interruption. Response was also assessed (1-month post-XRT brain MRI). Results: A total of 27 patients were enrolled. There were no DLTs observed in any dose groups. Grade 1 and 2 toxicities consisted of stomatitis, erythema, and alopecia. Of 24 patients evaluable for response, 1 patient had no evidence of disease, 3 patients had a PR; 9 patients had stable disease and 11 patients had progressive disease. Conclusions: Bortezomib can be combined at full dose with concurrent temozolomide and radiation therapy with minimal adverse effects. Correlative translational endpoints are still pending. The results observed justify further evaluation in a phase II setting.

[Table: see text]
A phase I study of SDX-102 for the treatment of patients with MTAP-deficient recurrent malignant gliomas
Authors: Phuphanich S. , Chamberlain M. , Mikkelsen T. , Ye X. , Grossman S. A. , Batchelor T. , Lesser G. , Fisher J. D. , Desideri S.
Published: March 2020

2063

Background: De novo purine biosynthesis entails two metabolic pathways of which one pathway is frequently impaired in cancer due to gene deletion of the rate limiting enzyme, methythioadenosine phosphorylase (MTAP). In MTAP-deficient cancers, SDX-102 inhibits purine biosynthesis by blocking the remaining synthetic pathway. This study was to determine the maximum tolerated dose (MTD), toxicity and pharmacokinetic activity of SDX-102 in the treatment of recurrent MTAP-deficient malignant gliomas. Methods: Eligible patients had recurrent supratentorial MTAP-deficient malignant gliomas treated previously with surgery, radiation and = 2 regimens of chemotherapy. Dose escalation was conducted separately for patients taking enzyme inducing anti-seizure drugs (EIASD+) and for those not (EIASD-). The starting dose in both groups was 80 mg/m2/day continuous infusion for 5 days every 3 weeks, cycle length was 3 weeks. Dose escalation was in a stepwise fashion in cohorts of three patients, up to a maximum dose of 125 mg/m2/day. Results: 118 patients were screened of which 39 (33%) had MTAP-deficient tumors. 21 patients (14 males/7 females) were enrolled between 9/17/04 and 3/17/06. Median age was 50 years (23–76); median KPS was 90 (60–100); 16 patients (76%) had GBM. Two dose levels of SDX-102 were tested in the EIASD+ group: 80 mg/m2/day (n=4) and 100 mg/m2/day (n=3), 3/3 dose limiting toxicity (DLT) were noted with grade 3 mucositis at 100 mg/m2/day , so in the EIASD+ group the MTD was 80 mg/m2/day. Three dose levels were tested in the EIASD- group: 80 mg/m2/day (n=4), 100 mg/m2/day (n=7), 1/3 patients had DLT (Grade 4 mucositis) at 100 mg/m2/day and the cohort was expanded for additional 3 patients without DLT noted; and 125 mg/m2/day (n=3) amongst whom no DLT was observed. No MTD was determined in the EIASD- group because the MTAP assay became unavailable through the sponsor. There were a range of 1–14 cycles administered in this patient population. Conclusions: SDX-102 infusion is safe and feasible in patients with recurrent MTAP-deficient malignant gliomas. The MTD in EIASD+ patients is 80 mg/m2/day. The EIASD-group MTD has not been determined however the highest dose tested is 125 mg/m2/day.

No significant financial relationships to disclose.
A phase II safety study of bevacizumab in patients with multiple recurrent or progressive malignant gliomas
Authors: Raizer J. J. , Gallot L. , Cohn R. , Chandler J. , Levy R. , Getch C. , Batjer H. , Marymont M. , Tellez C. , Mellot A. , Newman S.
Published: March 2020

2079

Introduction: Available treatment options for patients with recurrent MG are few. Recent trends have used target specific agents but none has been effective to date. A single agent trial was designed to determine the safety and efficacy of bevacizumab in patients with recurrent MG. Recently, bevacizumab and CPT-11 in combination have shown response rates of approximately 60%. Patients and Methods: All patients (pts) had to sign an IRB informed consent. All pts had to have at least two relapses. Pts had to be > 18 year of age with Karnofsky performance status of > 60. Adequate bone marrow, liver and renal function was required, as well as normal urine protein and creatinine. Patients were required to be on a non-enzyme inducing anti-convulsants. An MRI with perfusion was done at baseline (if patient consented) and then every 6 weeks. Patients continued on trial as long as they did not have tumor progression. Patients received bevacizumab 15 mg/kg every 3 weeks as a 60–90 minute infusion. Results: To date, 16 pts with recurrent MG have been treated. 14 pts had a glioblastoma (GBM) and 2 had an anaplastic oligodendroglioma (AO). Median number of doses given was 3 (range 1–12). No patient had an intracranial hemorrhage and the only significant toxicity was a DVT in a patient with prior DVT. Best responses per McDonald criteria were: PR in 2 pts, SD in 4 pts, PD in 3 pts and non-evaluable in 7 pts: 4 follow up imaging not done, 1 each with stable MRI after 2 doses but WD for non-compliance, clinical decline and patient’s choice. Results: Bevacizumab as a single agent given every 3 weeks at 15 mg/kg is safe. Partial responses and stable disease were seen in about 30 % of patients with follow up imaging but many patients are early in treatment. Our response rates to date are lower then previous reports of patients treated with CPT-11 and bevacizumab; this maybe due to the increased number of prior therapies, a different schedule of bevacizumab or the omission of CPT-11. Updated response rates, time to progression and overall survival will be presented.

[Table: see text]

No significant financial relationships to disclose.
PCR of immunoglobulin heavy-chain (IgH) complementary determining region III (CDRIII) for diagnosis of meningeal dissemination (MD) in primary CNS lymphoma (PCNSL): A prospective evaluation
Authors: Korfel A. , Fischer L. , Gleissner B. , Martus P. , Novrousian M. , Krümpelmann U. , Klasen H. , Kirchen H. , Thiel E.
Published: March 2020

2082

Background: The prognostic impact of MD in PCNSL is unclear. Cytomorphological examination of cerebrospinal fluid (CSF) cells is the gold standard for detection of MD. PCR for detection of a clonal B-cell population may represent a more sensitive and specific method for MD detection. Methods: CSF was collected by lumbar puncture before treatment in patients with newly diagnosed PCNSL of B cell type, histologically proven. CSF cytomorphological examination was performed by an experienced hematopathologist or neurologist immediately after sampling at the treating institution. A sample of native CSF was sent for PCR examination to our central moleculargenetic laboratory. Here, DNA from CSF cell pellets was extracted using commercially available kits. A seminested PCR of the IgH chain CDR III region was performed using the primers LJH in the first, VLJH in the second and FR3A in both PCR reactions. PCR products were subjected to an automated fluorescent fragment analysis (ALF) to detect a monoclonal vs. polyclonal pattern, and results were compared to conventional cytology. Results: From January 2001 to August 2006 CSF from 215 patients was collected. Here, data from the first 146 patients examined is presented ( Table ). MD was detected in 15 of 106 examined patients (14%) by cytomorphological evaluation and in 17 of 146 patients (11.6%) using PCR. In 8 patients with negative cytology the PCR product was monoclonal, and in 7 patients with positive cytology a polyclonal PCR product was found. Conclusion: The frequency of MD in PCNSL detected by PCR of the IgH CDR III region is low and comparable to that detected by cytomorphological evaluation. However, discordant PCR and cytology results are frequent. Thus, PCR analysis appears to be an important adjunct for MD diagnosis.

[Table: see text]

No significant financial relationships to disclose.
A clinical trial of autologous formalin-fixed tumor vaccine (AFTV) for patients with glioblastoma multiforme
Authors: Tsuboi K. , Ishikawa E. , Yamamoto T. , Takano S. , Matsumura A. , Ohno T.
Published: March 2020

2085

Background: This clinical pilot study is to investigate the safety, feasibility, plus clinical response of autologous formalin- fixed tumor vaccine (ATFV) in primary glioblastoma multiforme (GBM) patients. Methods: Eleven (8 recurrent and 3 initially treated) primary GBM patients were evaluated. AFTV was prepared from formalin-fixed tumor tissue or paraffin-embedded tissue and premixed with original adjuvant materials. A delayed-type hypersensitivity test (DTH) was performed before and after each course of ATFV treatment that comprised 3 vaccinations at a 5-site intradermal inoculation. In addition, immunohistochemical analysis of MIB-1, p53, and MHC class-I complex was performed on the tumor tissue to analyze the difference in the response to the treatment. Results: The treatment was well tolerated with only local induration and low-grade fever. Among the 11 patients, the best responses were 1 complete remission, 2 partial response, 1 no change, and 7 progressive disease. In this series, the median survival period was 7 months from the initiation of the AFTV treatment, and 3 of the 4 responders survived for more than 20 months after AFTV inoculation. DTH reactions, immunohistological analysis of p53 and MHC class-I complex, and patient status may be useful to predict the efficacy of this therapy. Conclusion: This study demonstrated that AFTV treatment is safe, feasible, and potentially beneficial. Further clinical investigation is highly desirable in order to improve the outcome of GBM patients.

No significant financial relationships to disclose.
Recurrent primary central nervous system lymphoma (PCNSL) treated with pemetrexed
Authors: Altman J. K. , Gallot L. , Cohn R. , Chandler J. , Levy R. , Getch C. , Marymont M. , Tellez C. , Raizer J. J.
Published: March 2020

2086

Introduction: Untreated, survival in PCNSL is approximately 2 months. However using high dose methotrexate based regimens, median survival is up to 60 months. A significant number of patients relapse. There is currently no standard therapy, but many regimens have been used with variable results. Pemetrexed is a multi-targeted anti-folate agent approved for first line treatment of malignant pleural mesothelioma and second-line for locally advanced or metastatic non-small cell lung cancer. A phase II trial was initiated for patients with recurrent gliomas, PCNSL or brain metastases. Pemetrexed, in addition to inhibiting dihydrofolate reductase, targets other sites of inhibition, giving it a broader spectrum of activty. This suggests that pemetrexed could be effective in PCNSL. Patients and Methods: The dose of pemetrexed used was 900 mg/m2 every 3 weeks; based on phase I data where the MTD was 800 mg/m2 in heavily pretreated patients and not reached in lightly pretreated patients. Patients received dexamethasone 4 mg twice daily on the day before, the day of, and the day after each infusion of pemetrexed and supplemental folic acid and B12. Eligibility criteria for PCNSL patients included failure of at least one prior chemotherapy regimen. Patients had to be > 18 year of age with KPS status of > 60. Adequate bone marrow, liver, and renal function were required. An MRI was done every 6 weeks and for patients who attained a CR, a maximum of six doses was given. Results: To date, five patients with recurrent PCNSL have been treated on this trial after signing IRB approved consent. Patient Characteristics Discussion: We report our experience of pemetrexed in 5 patients with recurrent PCNSL. Toxicity has been minimal except in the one patient who was heavily pretreated (including a stem cell transplant). Activity was seen in all patients but transient in two. Pemetrexed is active in relapsed PCNSL. The optimal dose and schedule need to be determined, as well as activity in a larger group of patients. We continue to enroll patients in this study.

[Table: see text]

No significant financial relationships to disclose.
Antitumor activity and biological effects of primary endocrine therapy with GnRH analog and letrozole in premenopausal women with locally advanced operable ER and PgR positive breast cancer
Authors: Torrisi R. , Ghisini R. , D'Alessandro C. , Bagnardi V. , Bottiglieri L. , Peruzzotti G. , Rocca A. , Goldhirsch A. , Colleoni M.
Published: March 2020

21008

Background: Aromatase inhibitors (AIs) in combination with GnRH analog (A) were never systematically studied in premenopausal women with hormone receptor positive locally advanced operable breast cancer. Methods: We investigated in a two stage phase II trial, the activity of GnRH A plus letrozole (LT), added when E2 levels were in the postmenopausal range, in premenopausal women with T2-T4b N0-N2, endocrine responsive (ER and PgR ≥ 10% of the cells) breast cancer. We also investigated at baseline and at surgery the expression of ERβ, MAPkinases (MAPKs), ERa, EGFR, Her-2/neu, either normal or phosphorylated (p). Results: Thirty-nine patients (pts) were enrolled and 35 (ER >50%, 29 (90%) ; Ki 67 = 20%, 17 (53%); cT2/3, 24/5) are evaluable for response (3 of whom did not receive LT for refusal or failure of achievement of ovarian suppression). There were 16 objective responders (46%, 95% CI 29.5- 62.5), 1 of whom had pCR (3%). Nineteen pts (50%) were stable. Breast conserving surgery became possible for 42% of the patients. Side effects were mild. Endocrine therapy was correlated with grade 2 hot-flashes and arthralgia in 43% and 6% of the patients, respectively. Molecular analysis was performed in 27 pts (13 responders and 14 non responders). Treatment induced a significant decrease of pERa an upregulation of ER-β, which were independent of response. No overexpression of EGFR and HER-2 was registered at baseline and after treatment. Conclusions: The combination of LT and GnRH A is feasible and effective in premenopausal women with locally advanced endocrine responsive operable breast cancer. A biological response to estrogen suppression was observed. Tailored endocrine therapy of longer duration merits further investigations in the preoperative setting.

No significant financial relationships to disclose.
Molecular identification of carcinoma of unknown primary (CUP) with gene expression profiling
Authors: Qu K. Z. , Li H. , Whetstone J. D. , Sferruzza A. D. , Bender R. A.
Published: March 2020

21024

Background: We previously reported a method for determining the site of tumor origin for CUP by comparing a 92- gene expression profile to that in a database created from 600 primary and metastatic tumor bank specimens of known origin. K-nearest neighbor analysis was used to determine the likelihood of an unknown patient specimen originating from a particular site with the likelihood assigned as a confidence level and reported as high, medium, low, or unclassified. Herein, we report the analysis of the gene expression profiling results from our initial series of clinical CUP specimens. Methods: We reviewed the results of 76 consecutive de-identified patient samples submitted to our laboratory for routine CUP testing. RNA was extracted from the formalin-fixed, paraffin-embedded (FFPE) tissue blocks and cDNA products used in a semi-quantitative real-time PCR to detect 87 tumor-associated genes and 5 reference genes. Gene expression data were then compared with our database and k-nearest neighbor analysis used to identify the 5 closest neighbors. If all 5 or 4/5 were the same, the result was classified as “high likelihood”, 3/5 = “moderate likelihood”, 2/5 = “low likelihood” and none matching was “unclassifiable”. Results: For the 76 clinical CUP samples tested, gene profiling analysis yielded high-likelihood predictions for 34 (45%), moderate for 12 (16%), low for 12 (16%), and unclassified for 14 (18%); amplification was inadequate for 4 (5%) samples. Overall, gene profiling analysis yielded classifiable predictions in 58 (76%) of clinical CUP samples. An occult carcinoid, metastatic melanoma and adenocarcinoma of the endocervix were identified and then found clinically using this assay. Conclusions: Our previous findings indicate that gene expression profiling can correctly identify the site of tumor origin in a high percentage of tumor bank samples. Data from the present study suggests that this approach can identify a primary site of tumor origin in 76% of actual clinical specimens from pathologist-submitted CUP cases.

No significant financial relationships to disclose.
Fas-670 polymorphism and prostate cancer
Authors: Lima L. , Calais da Silva F. M. , Calais da Silva F. E. , Morais A. , Lobo F. , Medeiros R.
Published: March 2020

21028

Background: The FAS/FASL system is one of the major pathways in apoptosis and is important to regulate cell proliferation and tumor cell growth. Functional promoter polymorphisms of FAS gene (FAS -670 A/G) alter the transcriptional activity. The role of FAS polymorphisms in prostate cancer has not been studied. Methods: DNA extracted from peripheral blood from 529 prostate cancer patients and from 247 healthy controls was analysed by Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) for FAS gene locus -670 genotypes. Results: We found that the AG and GG genotypes represent significantly protection (OR=0.41; confidence interval (CI): 0.26–0.65 and OR=0.39; CI: 0.21–0.74, respectively) for extracapsular invasion. Taken this genotypes together, a significantly protection was found for G allele carriers (OR=0.41; CI: 0.27–0.63). Conclusions: It is well known that G allele reduces the transcriptional activity of FAS gene. Fas exist as membrane bound and soluble forms and with opposite roles. They derive from the same gene by alternative splicing. Membrane Fas receptor trigger apoptosis and in other hand soluble Fas (sFas), which lacks transmembrane domain, binds to Fas ligand antagonizing Fas-Fas ligand apoptotic pathway. It is reported that serum sFas is elevated in prostate cancer and associated with advanced disease. Our results suggest that G allele may reduce sFas levels preventing the apoptotic inhibition caused by the soluble form.

No significant financial relationships to disclose.
CYP3A5*3 genotypes and advanced non-small cell lung cancer development
Authors: Nogal A. , Coelho A. , Araújo A. , Azevedo I. , Faria A. , Soares M. , Catarino R. , Medeiros R.
Published: March 2020

21030

Background: Lung cancer is the most common cancer in Europe (381.500 new cases in 2004) and the third in the U.S.A (172.570 new cases in 2005). Smoking is one of the major causes of lung cancer: there are many procarcinogens present in tobacco smoke that, when activated, contribute to the development of this disease. The CYP3A subfamily represents a group of enzymes responsible for the metabolism of many currently used drugs, exogenous carcinogens and endogenous molecules such as steroids. Two of the major enzymes in this family, CYP3A4 and CYP3A5, activate polycyclic aromatic hydrocarbons such as benzo[a]pyrene and other procarcinogens present in tobacco smoke. Functional polymorphisms, such as CYP3A5*3 (associated with the lack of the CYP3A5 protein), could alter individual susceptibility to lung cancer. The aim of our study was to evaluate the influence of this polymorphism in the development of lung cancer. Methods: DNA samples were extracted from peripheral blood cells of 203 patients with non small cell lung cancer, including 42 non- smokers and 156 smokers or former smokers (no data available for the other 5 patients) and 162 blood donors. The CYP3A5*3 polymorphism was analysed through PCR-RFLP (SspI). Analysis of data was performed using the computer software SPSS for windows. The odds ratio (OR) and its 95% confidence interval (CI) were calculated as a measure of the association between CYP3A5*3 genotypes and NSCLC progression. Results: We found significant statistical differences between the control group and the patients with advanced stages (III and IV) of epidermoid and undifferentiated NSCLC (p=0.04; OR = 0.48; 95% CI = 0.232–0.977). Conclusions: Individual differences in the metabolism of carcinogens may influence the susceptibility to cancer development and behaviour. Our preliminary results suggest that the carriers CYP3A5*3 polymorphism are at lower risk of developing advanced lung cancer. This is probably due to a decreased activation of procarcinogens present in tobacco smoke in result of the lack of CYP3A5 caused by the CYP3A5*3 polymorphism. This is consistent with the hypothesis of a cumulative effect of carcinogens on the aggressive behaviour of the disease.

No significant financial relationships to disclose.