scholarly journals OS2.2 Chemotherapy for spinal gliomas in adults

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii7-iii8
Author(s):  
D Gramatzki ◽  
J Felsberg ◽  
O Bähr ◽  
B Hentschel ◽  
M Westphal ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Combination Chemotherapy ◽  
Methylation Status ◽  
Response Rates ◽  
Myxopapillary Ependymoma ◽  
Diffuse Astrocytoma ◽  
Anaplastic Ependymoma ◽  
Who Grade ◽  
Response To Chemotherapy ◽  
Spinal Gliomas

Abstract BACKGROUND Chemotherapy is a treatment option in patients diagnosed with anaplastic gliomas or glioblastomas of the spinal cord, or with recurrent lower graded WHO spinal gliomas that are no longer amenable to local treatment. The low incidence of spinal cord gliomas, particularly in adults, limits the ability to perform clinical trials. The role of chemotherapy in these tumors has remained unclear. MATERIAL AND METHODS We performed a retrospective study of 22 patients diagnosed with spinal gliomas who were treated with chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by applying Response assessment in neuro-oncology criteria. Data on radiotherapy, as well as the number of neurosurgical interventions were taken into consideration. RESULTS Most patients were diagnosed with astrocytoma WHO grade I-IV (N=14), the remaining patients were diagnosed with ependymoma (N=8). Median follow-up from start of chemotherapy was 92 months (95% CI, 72.6–111.4). The O6-methylguanyl-DNA-methyltransferase(MGMT)promoter methylation status was available in tumors of 12 patients: 9 tumors (75%) had an unmethylated MGMTpromoter. More than 50% of the patients had more than one neurosurgical intervention. After prior surgery 10 patients in the first-line setting had chemotherapy combined with radiotherapy, while 3 patients received chemotherapy only. The remaining 9 patients had initially received radiation therapy and chemotherapy was given at time of recurrence. In patients diagnosed with astrocytoma mainly temozolomide (TMZ) was applied (N=10), while one patient received CCNU and three patients had combination chemotherapy. Patients diagnosed with ependymoma had hydroxyurea (N=1), CCNU (N=1), TMZ (N=3) or combination chemotherapy (N=3). In the group of patients who had chemotherapy combined with radiation, response rates were as follows: anaplastic astrocytoma 3 stable diseases (SD), glioblastoma 1 complete response (CR) and 1 SD, and anaplastic ependymoma 1 SD. After chemotherapy in the group of patients previously irradiated, the following response rates were observed: 1 SD in pilocytic astrocytoma, 1 SD in diffuse astrocytoma, 3 SD in myxopapillary ependymoma, and 2 SD and 1 partial response (PR) in anaplastic ependymoma. All other patients experienced progressive disease. There was no indication for a favorable prognostic role ofMGMTpromoter methylation. CONCLUSION Spinal cord gliomas represent a heterogeneous group of tumors. Survival outcomes in response to chemotherapy in adult spinal glioma patients vary substantially, but individual patients appear to derive benefit from chemotherapy.

EPCO-01. MOLECULAR PROFILING OF SPINAL CORD EPENDYMOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi1-vi1
Author(s):  
Erika Yamazawa ◽  
Shota Tanaka ◽  
Genta Nagae ◽  
Takayoshi Umeda ◽  
Taijun Hana ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dna Methylation ◽  
Methylation Status ◽  
Neurofibromatosis Type ◽  
Methylation Pattern ◽  
Who Grade ◽  
Spinal Ependymoma ◽  
Fresh Frozen ◽  
Spinal Cord Ependymoma ◽  
The Difference

Abstract BACKGROUND Ependymomas are currently classified into 9 subgroups by DNA methylation profiles. Although spinal cord ependymoma (SP-EPN) is distinct from other tumors, diversity within SP-EPN is still unclear. Here, we used transcriptomic and epigenomic profiles to investigate the diversity among Japanese SP-EPN cases. MATERIALS AND METHODS We analyzed 57 SP-EPN patients (32 males and 25 females, aged from 18 to 78 years, median: 52), including two cases of neurofibromatosis type 2, five cases of grade 3 (WHO grade). We obtained transcriptome (RNA-seq) and DNA methylation (Infinium Methylation EPIC array) data from fresh frozen specimens of SP-EPN resected at the University of Tokyo Hospital and our collaborative groups. RESULTS Three cases had a previous intracranial ependymoma operation. Hierarchical clustering of the DNA methylation data showed that these three cases of intracranial origin as a different cluster from spinal origin. The 45 grade 2 spinal ependymoma showed a relatively homogenous methylation pattern. However, the methylation status of HOX gene cluster regions is compatible with the segment of origin, which reflects the cells of origins are derived after the determination of segment identity. RNA sequencing of 57 cases revealed two subgroups within grade 2. Gene ontology analysis of differentially expressed genes suggested the difference in metabolic state such as rRNA translation and mitochondrial respiration between the two expression subgroups. CONCLUSION Epigenetic analysis indicated the accurate body segment origin of SP-EPN. We observed that metabolic states could divide grade 2 spinal cord ependymoma into 2 subgroups and will present the relationship to clinicopathological information.

Clinical, radiologic & prognostic profile of IDH wild type diffuse astrocytic glioma with molecular features of glioblastoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2557-2557
Author(s):  
Oluwatosin Akintola ◽  
Wesley Samore ◽  
Maria Martinez-Lage Alvarez ◽  
Elizabeth Robins Gerstner
Keyword(s):  
Clinical Trials ◽  
Methylation Status ◽  
Diffuse Astrocytoma ◽  
Tert Promoter Mutation ◽  
Promoter Mutation ◽  
Who Grade ◽  
Egfr Amplification ◽  
Astrocytic Glioma ◽  
Molecular Features ◽  
Tert Promoter

2557 Background: In 2018, The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recommended that IDH-wildtype diffuse astrocytic glioma Grade II/III with either EGFR amplification, combined whole chromosome 7 gain and whole chromosome 10 loss (+7/−10), or TERT promoter mutation should receive an integrated histological and molecular grade classification: Diffuse astrocytic glioma, IDH-wildtype with molecular features of glioblastoma, WHO grade IV. The natural history, radiologic characteristics and standard management for these patients has not been well described. They are typically excluded from clinical trials for WHO Grade IV gliomas. Methods: Adults diagnosed at Massachusetts General Hospital with IDH wildtype diffuse astrocytoma and EGFR amplification or TERT promoter mutation from 2011-2019 were identified. Demographics, functional status, radiologic features, MGMT promoter methylation status, time to progression, and overall survival were collected retrospectively. Qualitative MRI data was analyzed using the VASARI feature set. Response assessment was performed using the RANO criteria. Results: 50 patients were identified (table). 37/50 patients received standard Stupp protocol, 2/50 received hypofractionated radiotherapy with temozolomide, 6/50 received radiotherapy alone, and 1 patient received a MEK inhibitor. None were enrolled in clinical trials at diagnosis. mPFS was 10 months in the 47/50 with confirmed progression and mOS in the patients with confirmed deaths (40/50) was 17.5 months (4-47). 9/50 patients are alive with survival ranging 6-52 months. Conclusions: Outcomes for patients with molecularly defined GBM were variable. Analysis of the cohort to characterize factors that led to the observed variability is in progress. More studies on molecularly defined glioblastomas are required to better understand their behavior and to provide guidance for their inclusion or exclusion in clinical trials. [Table: see text]

Ependymoma of the spinal cord in children and adolescents: a retrospective series from the HIT database

2010 ◽  
Vol 6 (2) ◽  
pp. 137-144 ◽  
Author(s):  
Martin Benesch ◽  
Daniela Weber-Mzell ◽  
Nicolas U. Gerber ◽  
Katja von Hoff ◽  
Frank Deinlein ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Overall Survival ◽  
Adjuvant Treatment ◽  
Progression Free Survival ◽  
Gross Total Resection ◽  
Myxopapillary Ependymoma ◽  
Total Resection ◽  
Who Grade ◽  
Free Survival ◽  
Spinal Cord Ependymoma

Object Reports on spinal cord ependymoma in children are rare. The aim of this study was to evaluate the clinical spectrum, treatment, and outcome of children with primary ependymoma of the spinal cord who were registered in the database of the pediatric German brain tumor studies Hirntumor (HIT) '91 and HIT 2000. Methods Between 1991 and 2007, 29 patients (12 male and 17 female, median age at diagnosis 13.6 years) with primary spinal cord ependymoma (myxopapillary ependymoma WHO Grade I, II, and III tumors in 6, 17, and 6 patients, respectively) were identified. Four patients had neurofibromatosis Type 2. Results With a median follow-up of 4.2 years (range 0.48–15 years), 28 patients (96.6%) were alive. Seven patients (24.1%) developed progressive disease or relapse, 2 after gross-total resection (GTR) and 5 after incomplete resection or biopsy. One patient with anaplastic ependymoma (WHO Grade III) died 65 months after diagnosis of disease progression. Primary adjuvant treatment (radiotherapy, chemotherapy, or both) was used in 8 (50%) of 16 patients following GTR and in 9 (82%) of 11 patients who underwent less than a GTR. Three additional patients were treated adjuvantly following progression. Estimated progression-free survival and overall survival rates at 5 years were 72.3% (95% CI 50%–86%) and 100%, respectively. Progression-free survival at 5 years is 84.4% (95% CI 50%–96%) for patients following GTR compared with 57.1% (95% CI 25%–69%) for patients who achieved a less than GTR (p = 0.088, log-rank test). A high relapse incidence (4 of 6) was observed among patients with myxopapillary ependymoma. Conclusions Gross-total resection is the mainstay of treatment for patients with primary spinal cord ependymoma and may be achieved in about 50% of the patients using modern surgical techniques. Primary adjuvant treatment was commonly used in children with spinal cord ependymoma irrespective of the extent of resection or tumor grade. The impact of adjuvant treatment on progression-free and overall survival has to be investigated in a prospective trial.

Quantitative analysis of 06-methylguanine-DNA methyltransferase (MGMT) promoter methylation in patients with low-grade gliomas

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2069-2069
Author(s):  
A. F. Ochsenbein ◽  
A. D. Schubert ◽  
E. Vassella ◽  
L. Mariani
Keyword(s):  
Promoter Methylation ◽  
Tumor Response ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Low Grade ◽  
Who Grade ◽  
Low Grade Gliomas ◽  
Response To Chemotherapy ◽  
Mgmt Promoter ◽  
Grade Ii

2069 Background: Loss of heterozygosity (LOH) on the chromosomes 1p and 19q is associated with sensitivity to alkylating agents like temozolomide (TMZ) in patients with low-grade gliomas; whether methylation of the MGMT-promoter, a predictive factor in glioblastoma patients, also correlates with tumor response to TMZ in low-grade gliomas is unclear. Methods: We performed a retrospective analysis of patients with histologically verified low-grade gliomas (WHO Grade II) who were treated with TMZ for tumor progression at our hospital between November 1999 and November 2007. Objective tumor response was assessed by MRI at 6-month intervals. LOH of microsatellite markers on chromosomes 1p and 19q was determined by polymerase chain reaction (PCR) amplification of the matched pairs of blood and tumor DNA. A methylation-specific, primer extension based PCR method was developed to quanitatively assess the MGMT methylation status in the tumour tissue. Results: Twenty-two patients with a median age of 53 years (range 27–72) were included in the study; 59% were male. Seven patients had prior surgical resection of the tumor. Histological classification revealed 10 oligodendrogliomas, 7 oligoastrocytomas, and 5 astrocytomas. All patients were treated with TMZ 200mg/m2 day1–5 in a 4 wk cycle. Grade 3–4 hematological toxicity occurred in 32% of the patients (9% leucopenia, 23% thrombocytopenia). The progression free survival was 32 months. Combined LOH 1p and 19q was found in 14 pts; 1 patient had LOH 1p alone and 1 patient LOH 19q alone. The LOH status could not be determined in two patients and was normal in the remaining four. MGMT promoter methylation was detectable in 20 pts by conventional PCR and quantitative analysis revealed a methylation status between 12%-100%. The volumetric response to chemotherapy analyzed after 6 months by MRI correlated with the level of MGMT promoter methylation (p = 0.012). Conclusions: Quantitative methylation-specific PCR of the MGMT promoter correlates with radiological response to chemotherapy with temozolomide in WHO grade II gliomas. No significant financial relationships to disclose.

scholarly journals Molecular diagnostics helps to identify distinct subgroups of spinal astrocytomas

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Annamaria Biczok ◽  
Felix L. Strübing ◽  
Julia M. Eder ◽  
Rupert Egensperger ◽  
Oliver Schnell ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Molecular Markers ◽  
Prognostic Significance ◽  
The Elderly ◽  
Molecular Profile ◽  
Diffuse Astrocytoma ◽  
Molecular Alterations ◽  
High Grade Astrocytoma ◽  
Dismal Prognosis ◽  
Few Data

AbstractPrimary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations in association with the clinical course. Histology and genome sequencing was performed in 26 spinal astrocytomas operated upon between 2000 and 2020. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations. Histology and NGS allowed the distinction of 5 tumor subgroups: glioblastoma IDH wildtype (GBM); diffuse midline glioma H3 K27M mutated (DMG-H3); high-grade astrocytoma with piloid features (HAP); diffuse astrocytoma IDH mutated (DA), diffuse leptomeningeal glioneural tumors (DGLN) and pilocytic astrocytoma (PA). Within all tumor entities GBM (median OS: 5.5 months), DMG-H3 (median OS: 13 months) and HAP (median OS: 8 months) showed a fatal prognosis. DMG-H3 tend to emerge in adolescence whereas GBM and HAP develop in the elderly. HAP are characterized by CDKN2A/B deletion and ATRX mutation. 50% of PA tumors carried a mutation in the PIK3CA gene which is seemingly associated with better outcome (median OS: PIK3CA mutated 107.5 vs 45.5 months in wildtype PA). This exploratory molecular profiling of spinal cord astrocytomas allows to identify distinct subgroups by combining molecular markers and histomorphology. DMG-H3 tend to develop in adolescence with a similar dismal prognosis like GBM and HAP in the elderly. We here describe spinal HAP with a distinct molecular profile for the first time.

scholarly journals CTNI-22. RETROSPECTIVE ANALYSIS OF THE COMBINED TREATMENT OF VINCRISTINE, ACNU, CARBOPLATIN AND INTERFERON-β PLUS RADIOTHERAPY (VAC-FERON-R)IN PATIENTS WITH DIFFUSE ASTROCYTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii47-ii47
Author(s):  
Yoshiki Arakawa ◽  
Yasuhide Makino ◽  
Takeshi Kawauchi ◽  
Masaharu Tanji ◽  
Yohei Mineharu ◽  
...  
Keyword(s):  
Combined Treatment ◽  
Diffuse Astrocytoma ◽  
Wild Type ◽  
Interferon Β ◽  
Mutant Type ◽  
Who Grade ◽  
Integrated Diagnosis ◽  
Significant Difference ◽  
Favorable Clinical Outcome ◽  
The Impact

Abstract OBJECTIVE Diffuse astrocytomas are classified as WHO grade II and its median overall survival (mOS) is 10 to 11 years. The efficacy of chemoradiation in the high-risk feature has been reported. The prognosis is associated with IDH and TERT promoter (TERTp) mutations. Here, we retrospectively analyzed the patients with diffuse astrocytoma treated with vincristine, ACNU, carboplatin and interferon-β plus radiotherapy (VAC-feron-R)in our institute. PATIENTS AND METHODS Between December 2003 to January 2016, 44 patients were diagnosed as diffuse astrocytoma with integrated diagnosis of histological and molecular analysis. The average age was 43.1 years (22–71 years). They received VAC-feron-R as initial treatment in our institute. We analyzed the IDH1/2 and the TERTp mutation using Sangar sequencing and determined the 1p/19q codeletion by the fluorescence in situ hybridization or the multiplex ligation-dependent probe amplification. RESULTS Median follow-up period was 76.5 months, mPFS was 126 months, mOS did not reach, and 10-year survival rate was 60%.IDH status was determined in 29 patients, 9 mutant and 20 wild types. There was no significant difference in PFS and OS between the two groups. TERTp status was determined in 18 patients with IDH wild type, 6 mutant and 12 wild types. mPFS of patients with TERTp wild type did not reach, but that with TERTp mutant type was 34.5 months (p = 0.0356). CONCLUSION Compared with previous clinical studies, VAC-feron-R showed a favorable clinical outcome in diffuse astrocytoma. The impact of TERTp status on prognosis was identified but not IDH status in this cohort.

scholarly journals INNV-07. THE KOREAN SOCIETY FOR NEURO-ONCOLOGY (KSNO) GUIDELINE FOR GLIOMAS: VERSION 2019.01

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi131-vi132
Author(s):  
Young Zoon Kim ◽  
Chae-Yong Kim ◽  
Do Hoon Lim ◽  
Dong-Sup Chung
Keyword(s):  
Anaplastic Astrocytoma ◽  
Poor Performance ◽  
Diffuse Astrocytoma ◽  
Molecular Feature ◽  
Who Grade ◽  
Korean Society ◽  
Brain Radiotherapy ◽  
Adjuvant Temozolomide ◽  
Radiotherapy Alone ◽  
Temozolomide Chemotherapy

Abstract BACKGROUND There was no practical guideline for the management of patients with central nervous system (CNS) tumor in Korea for many years. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, started to prepare a guideline for CNS tumors from February 2018. METHODS The Working Group was composed of 35 multidisciplinary medical experts in Korea. References were identified through searches of PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL using specific and sensitive keywords as well as combinations of keywords. RESULTS First, for the glioblastoma as WHO Grade IV Gliomas, the maximal safe resection if feasible is recommended. Patients aged ≤ 70 years with good performance should be treated by concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide chemotherapy (Stupp’s protocol) or standard brain radiotherapy alone. However, those with poor performance should be treated by hypofractionated brain radiotherapy (preferred) ± concurrent or adjuvant temozolomide or temozolomide alone (Level III) or supportive treatment. Second, for the WHO Grade III Gliomas, patients with anaplastic astrocytoma, IDH-mutant should be treated by standard brain radiotherapy followed by adjuvant temozolomide chemotherapy, or Stupp’s protocol, or standard brain radiotherapy with neoadjuvant or adjuvant PCV chemotherapy, or Standard brain radiotherapy alone (Level III). However, those anaplastic astrocytoma, IDH-wildtype should be treated by the protocol for glioblastoma. Third, for the WHO Grade II Gliomas, patients with diffuse astrocytoma, IDH-wildtype without molecular feature of glioblastoma should be treated by standard brain radiotherapy and adjuvant temozolomide chemotherapy (Level III), or standard brain radiotherapy alone, or observation. And patients with diffuse astrocytoma IDH-mutant and oligodendroglioma (IDH-mutant and 1p/19q codeletion) should be treated according to the risk factors. CONCLUSION The recent KSNO’s guideline recommends that glioma should be treated according to the molecular as well as histological features. However, the practice can be limited by the National Insurance for Health in Korea.

scholarly journals RARE-01. NATIONWIDE TRENDS IN MANAGEMENT OF ADULT MYXOPAPILLARY EPENDYMOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi221-vi221
Author(s):  
Daphne Baracena ◽  
Patrick Kelly ◽  
Arpine Khudanyan ◽  
Claire Turina ◽  
Jerry Jaboin ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Progression Free Survival ◽  
Age At Diagnosis ◽  
Myxopapillary Ependymoma ◽  
High Survival ◽  
Disease Entity ◽  
Who Grade ◽  
First Line Therapy ◽  
Primary Means ◽  
The Impact

Abstract INTRODUCTION Myxopapillary ependymomas (MPE) are WHO Grade I ependymomas that occur in the spine and have an annual incidence of 0.05–0.08 per 100,000 people. Maximal, safe surgical resection is the recommended first line therapy. Due to the rarity of the disease there is a relatively poor understanding of the use of radiotherapy (RT) in the management of disease. METHODS Using the National Cancer Database (NCDB), we analyzed the patterns and impact of RT on spinal MPE in adults diagnosed between 2002 and 2016. RESULTS Of 753 qualifying cases, the majority of patients underwent resection (n = 617, 81.9%). A relatively small portion received RT (n = 103, 13.3%) with most receiving RT after surgical resection (n = 98, 95.1%). The likelihood of patients to undergo resection and RT was significantly associated with patient age at diagnosis (p = 0.002), tumor size (p < 0.001), and race (p = 0.017). Chemotherapy was not widely utilized (only 0.27% of patients). DISCUSSION Although practice patterns can be highlighted from this 15-year analysis, given the high survival in this disease entity, progression-free survival (PFS) is an important outcome not available from this database. As expected, surgery is the primary means to manage adult MPE. For spinal MPE, it is understood that gross total resection (GTR) should be attempted whenever possible as GTR has been associated with improved PFS in several studies. RT and chemotherapy are used infrequently. In univariate analyses, RT was employed more often for larger tumor sizes, Latino/Hispanic ethnicity, and younger age at diagnosis. The impact of RT on overall survival is indeterminate given the 1.6% death rate in the cohort. Analyses of the impact of RT on PFS in a larger database would be beneficial for determining an algorithm for post-operative and definitive radiotherapy in this disease entity.

Safety and Efficacy of Using a Single Agent or a Phase II Agent Before Instituting Standard Combination Chemotherapy in Previously Untreated Metastatic Breast Cancer Patients: Report of a Randomized Study—Cancer and Leukemia Group B 8642

1999 ◽  
Vol 17 (5) ◽  
pp. 1397-1397 ◽  
Author(s):  
Mary E. Costanza ◽  
Raymond B. Weiss ◽  
I. Craig Henderson ◽  
Larry Norton ◽  
Donald A. Berry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Combination Chemotherapy ◽  
Single Agent ◽  
Metastatic Breast ◽  
Response Rates ◽  
Breast Cancer Patients ◽  
Safety And Efficacy

PURPOSE: We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients. PATIENTS AND METHODS: A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF. RESULTS: The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm. CONCLUSION: The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer.

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