Malignant Gliomas as Second Neoplasms in Pediatric Cancer Survivors: Neuropathological Study.

This study presents a unique series of malignant supratentorial gliomas in children previously cured from non-CNS primary cancer. On neuroimaging these tumors were not specific, so the patients were suspected of cerebral recurrence of their primary neoplasm: leukemia in four children and sarcoma in one child. Histologically, the group contained four glioblastomas and one anaplastic astrocytoma. Three patients underwent neurosurgical resection, while the other two underwent stereotactic diagnostic biopsy only. Despite combined oncological treatment, four children died during 20 months, and only one glioblastoma patient continued to live for another twelve years. Microscopically, the neoplasms consisted of small cells with some morphologic features of astrocytic lineage, having scanty or prominent processes. Microvascular proliferation and focal or diffuse necrosis were encountered in four cases. The GFAP reactivity in neoplastic cells was low or nil, together with the expression of Olig2, vimentin, and nestin. In two cases a subpopulation of synaptophysin-positive cells was present. Molecular immunohistochemical profiling revealed the expression of phosphorylated forms of PI3Kp110 and AKT, in parallel to a strong PTEN and p53 positivity. The tumors were of IDH1R132H-wild type and immunoreactive for ATRX, HER3, and EGFR. Secondary malignant gliomas in pediatric cancer survivors pose a diagnostic challenge. The present study shows that these tumors are of IDH wild type, PI3K/AKT-activated, having no PTEN and EGFR mutations. Therefore, the biopsy of brain tumors in such patients is crucial both for accurate diagnosis and material preservation for molecular typing.

Outcome and prognostic factors in 110 consecutive patients with primary uterine leiomyosarcoma: A Rare Cancer Network study.

OBJECTIVE: Primary uterine leiomyosarcomas (ULMS) are rare, and the optimal treatment is controversial. We aimed to assess the outcome and prognostic factors in a multicenter population of women treated for primary ULMS. METHODS: We retrospectively collected data of 110 women treated in 19 institutions of the Rare Cancer Network (RCN). Inclusion criteria consisted of a pathology report confirming the diagnosis of ULMS, aged 18-80 years, complete International Federation of Gynecology and Obstetrics (FIGO) stage information, complete information on treatment, and a minimum follow-up of 6 months. Local control (LC) and locoregional control (LRC), overall survival (OS) and disease-free survival (DFS) rates were computed using the Kaplan-Meier method. Univariate analysis was implemented using the log rank test, and multivariate analysis using the Cox model. RESULTS: All patients underwent surgery. Seventy-five patients (68%) received adjuvant radiotherapy (RT), including brachytherapy in 18 (16%). Seventeen patients (15%) received adjuvant chemotherapy. Median follow-up was 58 (range, 6-240) months. Five-year OS and DFS rates were 50% and 34%, and LC and LRC rates were 88% and 72%, respectively. On multivariate analysis, independent favorable prognostic factors were younger age, FIGO stage I, small tumor size, previous uterine disease, and no vascular invasion for OS and DFS. FIGO stage was the only favorable factor influencing LRC. Adjuvant local or systemic treatments did not improve the outcomes. Eight patients treated with RT presented a grade 3 acute toxicity, and only one patient with grade 3 late toxicity. CONCLUSIONS: In this large population of primary ULMS patients, we found good results in terms of LC and LRC. Nevertheless, OS remains poor, mainly due to the occurrence of distant metastases. An early diagnosis seemed to improve the prognosis of the patients. Adjuvant local or systemic treatments, or more aggressive surgical procedures such as the Wertheim procedure, did not seem to impact the outcome.

An open label phase II study evaluating first-line EGFR tyrosine kinase inhibitor erlotinib in non-small cell lung cancer patients with tumors showing high EGFR gene copy number.

BACKGROUND: First-line treatment with epidermal growth factor receptor (EGFR) inhibitors in NSCLC is effective in patients with activating EGFR mutations. The activity of erlotinib in patients harboring high EGFR gene copy number has been considered debatable. PATIENTS AND METHODS: A multicenter, open-label, single-arm phase II clinical trial was performed to test the efficacy of erlotinib in the first-line treatment of NSCLC patients harboring high EGFR gene copy number defined as ≥4 copies in ≥40% of cells. FINDINGS: Between December 2007 and April 2011, tumor samples from 149 subjects were screened for EGFR gene copy number by fluorescence in-situ hybridization (FISH), Out of 49 patients with positive EGFR FISH test, 45 were treated with erlotinib. Median PFS in the intent-to-treat population was 3.3 months (95%CI: 1.8-3.9 months), and median overall survival was 7.9 months (95% CI: 5.1-12.6 months). Toxicity profile of erlotinib was consistent with its known safety profile. The trial was stopped prematurely at 63% of originally planned sample size due to accumulating evidence that EGFR gene copy number should not be used to select NSCLC patients to first-line therapy with EGFR TKI. Data on erlotinib efficacy according to EGFR, KRAS and BRAF mutations are additionally presented. INTERPRETATION: This trial argues against using high gene copy number for selection of NSCLC patients to first-line therapy with EGFR TKIs. The study adds to the discussion on efficacy of other targeted agents in patients with target gene amplified tumors.

DNA double-strand break repair genes and oxidative damage in brain metastasis of breast cancer.

BACKGROUND: Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood. METHODS: Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis-specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group). RESULTS: Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression. CONCLUSIONS: BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species-mediated genotoxic stress in the metastatic brain.

Baseline quality of life and performance status as prognostic factors in patients with extensive-stage disease small cell lung cancer treated with pemetrexed plus carboplatin vs. etoposide plus carboplatin.

BACKGROUND: Small cell lung cancer (SCLC) is associated with poor prognosis due to its early metastatic potential and lack of improved outcomes with newer cytotoxic agents. Identifying factors associated with clinical outcomes can help clinicians determine which patients are more likely to benefit from therapy. Functional Assessment of Cancer Therapy (FACT) subscales and Eastern Cooperative Oncology Group performance status (ECOG PS) were retrospectively analyzed as prognostic factors for overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage disease (ED)-SCLC. METHODS: Using data from a Phase III trial of pemetrexed-carboplatin vs. etoposide-carboplatin, the effect of the prognostic factors on OS and PFS was analyzed via Cox models. The Kaplan-Meier method was used to estimate OS and PFS parameters for the prognostic subgroups (defined by baseline FACT scores and ECOG PS). RESULTS: Patients with higher baseline FACT-General (FACT-G) score (≥ median) had significantly higher OS (hazard ratio [HR]=0.62, P<.0001) and PFS (HR=0.83, P=.032) compared with patients with lower FACT-G score (