Comparison of tumor immune environment between newly diagnosed and recurrent glioblastoma including matched patients.

PURPOSE: Glioblastoma (GBM) is the most lethal primary brain tumor in adult patients. The disease progression, response to chemotherapy and radiotherapy at initial diagnosis, and prognosis are profoundly associated with the tumor microenvironment, especially the features of tumor-infiltrating immune cells (TII). Recurrent GBM is even more challenging to manage. Differences in the immune environment between newly diagnosed and recurrent GBM and an association with tumor prognosis are not well defined. METHODS: To address this knowledge gap, we analyzed the clinical data and tissue specimens from 24 GBM patients (13 at initial diagnosis and 11 at recurrence). The expression levels of multiple immunobiological markers in patients' GBM at initial diagnosis versus at recurrence were compared, including five patients with both specimens available (paired). The distribution patterns of TII were evaluated in both the intratumoral and perivascular regions. RESULTS: We found that tumors from recurrent GBM have significantly more tumor-infiltrating lymphocytes (TILs) and macrophages and higher PD-L1 and PD-1 expression than tumors at primary diagnosis and benign brain specimens from epilepsy surgery. The pattern changes of the TILs and macrophages of the five paired specimens were consistent with the unpaired patients, while the CD8 to CD4 ratio remained constant from diagnosis to recurrence in the paired tissues. The levels of TILs, macrophages, PD-1 or PD-L1+ cells at initial diagnosis did not correlate with OS. TILs, macrophages, and PD-1+ cells were increased in recurrent tumors both in intratumoral and perivascular areas, with higher distribution levels in intratumoral than perivascular regions. Higher CD4 or CD8 infiltration at recurrence was associated with a worse prognosis, respectively. CONCLUSIONS: Our study elucidated that TIL and TAM tend to accumulate in perivascular region and are more abundant in recurrent GBM than newly diagnosed GBM.

Efficacy of sequential radiation and chemotherapy in treating glioblastoma with poor performance status.

INTRODUCTION: While the current standard of care after maximal safe resection for glioblastoma (GBM) is concomitant radiation and chemotherapy, the ideal therapy for patients with poor performance status remains in question due to concerns about treatment tolerance. We sought to evaluate an alternative regimen, sequential radiation and chemotherapy, to assess its efficacy as a treatment option for poorly performing patients. METHODS: We performed a retrospective analysis using the 2015 National Cancer Database in which the survival of patients with a KPS ≤ 70 who received sequential radiation and chemotherapy were compared to those who received radiation therapy alone. Survival outcomes were compared using Kaplan-Meier curves with log rank testing and Cox proportional hazard regression. RESULTS: There were 84 patients analyzed in this study, all of whom had a KPS between 10 and 70. Of those analyzed, 73.8% received radiation therapy alone, and 26.2% received sequential radiation and chemotherapy. There was no difference in survival between the two treatment groups (p = 0.84). Patient age of 70 years or older (n = 31) was associated with decreased survival (HR 1.06 per year, p < 0.0001), regardless of KPS and a KPS of < 70 correlated with a near-significant trend toward worse survival (HR 1.63, p = 0.06). CONCLUSIONS: Treatment with sequential radiation and chemotherapy in poorly performing patients is not associated with an advantage in survival outcome when compared to radiation alone in GBM patients with poor performance status.

Natural products: a hope for glioblastoma patients.

Glioblastoma (GBM) is one of the most aggressive malignant tumors with an overall dismal survival averaging one year despite multimodality therapeutic interventions including surgery, radiotherapy and concomitant and adjuvant chemotherapy. Few drugs are FDA approved for GBM, and the addition of temozolomide (TMZ) to standard therapy increases the median survival by only 2.5 months. Targeted therapy appeared promising in in vitro monolayer cultures, but disappointed in preclinical and clinical trials, partly due to the poor penetration of drugs through the blood brain barrier (BBB). Cancer stem cells (CSCs) have intrinsic resistance to initial chemoradiation therapy (CRT) and acquire further resistance via deregulation of many signaling pathways. Due to the failure of classical chemotherapies and targeted drugs, research efforts focusing on the use of less toxic agents have increased. Interestingly, multiple natural compounds have shown antitumor and apoptotic effects in TMZ resistant and p53 mutant GBM cell lines and also displayed synergistic effects with TMZ. In this review, we have summarized the current literature on natural products or product analogs used to modulate the BBB permeability, induce cell death, eradicate CSCs and sensitize GBM to CRT.

Safety of long-term anticoagulation in patients with brain metastases.

Anticoagulation is thought to be associated with the risk of intracranial hemorrhage (ICH) in patients with brain metastases; however, the data on this topic are limited. This study was conducted to determine the incidence of ICH associated with anticoagulant use in adult patients with brain metastases. Consecutive patients with brain metastases occurring from 2006 to 2014 were identified from a single-institution database. Long-term anticoagulant therapy was defined as outpatient anticoagulation therapy of > 1 month. Chi-square tests and Fisher's exact test were used to compare rates of ICH by groups. This cohort included 125 patients with brain metastases. Of these, 64 had primary of non-small cell lung cancer (51.2%). Of these patients, 12/125 (9.6%) patients developed ICH. Neither the primary tumor site nor the number of brain metastases was associated with the development of ICH. ICH incidence was not associated with the use of anticoagulant therapy, with 8/67 (11.94%) patients on outpatient anticoagulation and 4/58 (6.9%) not on anticoagulation experiencing ICH (p = 0.33). The type of treatment did not significantly influence ICH, although those having combined WBRT and SRS were numerically more likely to experience ICH (4/15; 26.67%) of this cohort. In patients on enoxaparin, there was no difference in the incidence of ICH for daily versus twice-daily dosing (p = 1.0). Long-term anticoagulant use is not associated with an increased incidence of ICH in patients with intracranial metastases.

EGFR monoclonal antibodies in locally advanced head and neck squamous cell carcinoma: What is their current role?

Treatment options for locally advanced squamous cell carcinoma of the head and neck (SCCHN) include either surgical resection followed by radiation or chemoradiation, or definitive chemoradiation for which single-agent cisplatin is the best studied and established. The increasing understanding of the molecular biology of SCCHN has led to an interest in the development of targeted therapies. The epidermal growth factor receptor (EGFR) is over-expressed in nearly 80-90% of cases of SCCHN and correlates with poor prognosis and resistance to radiation. Preclinical evidence showed that blocking EGFR restores radiation sensitivity and enhances cytotoxicity. This finding led to clinical trials evaluating this class of agents and the approval of cetuximab in combination with radiation for the treatment of locally advanced SCCHN. This review is focused on the anti-EGFR monoclonal antibodies and their role either with radiotherapy or chemoradiation in unresectable LA SCCHN.

Outcomes for patients with anaplastic astrocytoma treated with chemoradiation, radiation therapy alone or radiation therapy followed by chemotherapy: a retrospective review within the era of temozolomide.

Treatment for anaplastic astrocytoma (AA) is controversial. To assess three primary treatment approaches, patients from a single institution were retrospectively evaluated. To represent modern treatment selection, patients diagnosed with AA from December 2003 to December 2009 were selected. Those with insufficient data, incomplete pathology, and transformation or reclassification to glioblastoma in fewer than 6 months were excluded. A total of 163 patients were included in the final analyses. Median follow-up time was 4.2 years (range 0.5-7.8 years). Median age and Karnofsky performance status at diagnosis were 39.2 years and 90, respectively. 23.6 % of patients underwent biopsy, and 72.2 % underwent resection. Approximately 31 % received concurrent chemoradiation (CRT), 26.1 % had radiation therapy alone (RT), 38.2 % had radiation therapy followed by chemotherapy (RT-C), and 3 % were treated only with chemotherapy. Temozolomide was used almost exclusively during CRT (94.2 %) and adjuvantly. A median of 9.5 cycles of adjuvant chemotherapy was given. The combination of radiation and chemotherapy, either concurrent or sequential trended toward a higher rate of radiation necrosis. Median progression free survival (PFS) favored RT (not reached) over CRT (1.5 years) and RT-C (3.6 years) adjusted for pairwise comparison (p = 0.033, p = 0.050). Median overall survival (OS) was 5.7 years, and did not differ significantly by treatment group. OS for patients with AA did not vary by initial treatment selection. Although the longer PFS in those receiving RT versus CRT may be confounded by pseudoprogression, the equivalent OS among groups supports RT.

Atypical teratoid/rhabdoid tumors in adults: a case report and treatment-focused review.

UNLABELLED: Atypical teratoid/rhabdoid tumor is predominantly a childhood tumor and has only been rarely reported in adults; therefore, treatment regimens are often extrapolated from the pediatric experience. Typically, children are treated with craniospinal radiation therapy which is often followed by systemic chemotherapy. Employing pediatric regimens to treat this tumor in adult patients poses a particular risk for myelosuppression, as the prescribed doses in pediatric protocols exceed those tolerated by adults, and conventional craniospinal radiation can be associated with prolonged myelotoxicity and a depletion of the bone marrow reserve in vertebrae of adults. Here we present a case of a woman with a pineal region atypical teratoid/rhabdoid tumor, an unusual adult cancer presenting in an atypical location. This is followed by a review of the disease in adult patients with an emphasis on treatment and suggestions to minimize myelotoxicity. KEYWORDS: Atypical rhabdoid tumor; AT/RT; Pineal tumor; Adult.

Cerebellar glioblastoma: a retrospective review of 21 patients at a single institution.

Primary cerebellar glioblastoma (CGB) comprises only 0.4-3.4% of all intracranial glioblastoma. The impact of surgical resection on survival and the efficacy of adjuvant therapies are uncertain as CGB is underrepresented in most studies. To elucidate prognostic factors we performed a single-institutional review of the largest series to date of CGB. The University of Texas MD Anderson Cancer Center database was reviewed from 1990 to 2010. Twenty-one consecutive patients met criteria for inclusion. The Kaplan-Meier product limit method was used to estimate overall survival (OS) and progression-free survival (PFS); groups were compared using the log-rank statistic. The multivariate Cox proportional hazards models were fitted to examine the association of resection with OS and PFS adjusted for other clinical variables. The median age was 39.9 years, and Karnofsky performance status (KPS) was ≥ 80 in 61.5% of patients. The mean extent of resection for contrast enhancement (EOR-CE) was 93.8% (SD = 10.4%; median = 100%), and the median follow-up was 18.4 months (range 1.5-116.1 months). There was no significant association of EOR with OS or PFS. On univariate analysis the presence of leptomeningeal disease (LMD) was associated with a worse OS (6.1 vs. 24.1 months; P = 0.0001) and PFS (3.3 vs. 9 months; P = 0.019). Patients who had adjuvant chemotherapy (CT) had extended PFS (10.1 vs. 2.8 months; P < 0.0001). Adjustment for the presence of leptomeningeal disease (LMD) tended toward an increased risk of progression (HR = 3.46; 95% confidence interval [CI], 0.83-14.5; P = 0.09) and was associated with a significantly increased risk of death (HR = 15.2; 95% CI, 1.3-180; P = 0.03). Having received adjuvant chemotherapy was associated with a decreased risk of progression (HR = 0.02; 95% CI, 0-0.26; P = 0.003). The presence of LMD is a critical factor in the clinical behavior of CGB resulting in markedly decreased OS and PFS. Adjuvant CT resulted in increased PFS but did not significantly affect OS. This was due to a lack of a sizable cohort who did not receive chemotherapy. Furthermore, three of the CT-naïve patients received CT at first progression. In the context of the high EOR in this study, an OS of 18.4 months was achieved.

Targets for therapy in ependymoma.

Ependymomas are among the rarest type of glioma and display significant heterogeneity based on patient age and tumor location. Treatment strategies include surgery and radiation, but the use of chemotherapy remains more controversial. Chemotherapy has been widely utilized in the pediatric population due to more aggressive disease in this cohort, and has become of interest in the adult population as well. Unfortunately, relapses are common, and responses to cytotoxic chemotherapy are often disappointing. As a result, attention has turned to specific targets in the pathogenesis of ependymoma. This paper summarizes the current understanding of promising molecular pathways and targets under study for future application in ependymoma.

Pancytopenia due to iron deficiency worsened by iron infusion: a case report.

INTRODUCTION: Iron deficiency anemia is commonly associated with thrombocytosis, although thrombocytopenia has been reported in occasional patients with iron-deficiency anemia. Much less common is the development of thrombocytopenia following replenishment of iron stores. CASE PRESENTATION: We present the unusual case of a 39 year old African American female Jehovah's Witness who presented with a 10 month history of menorrhagia and pancytopenia. Laboratory investigations confirmed a severe iron deficiency. Since blood transfusion was unacceptable to her, she was started on intravenous iron replacement therapy. This precipitated a sudden drop in both her platelet and white blood cell counts. Histopathological examination of the bone marrow revealed a hypercellular marrow with orderly trilineage hematopoiesis, iron deficiency anemia, granulocytic hyperplasia, and mild megakaryocytic hypoplasia. Both her white blood cell and platelet counts recovered uneventfully with continuing iron supplementation. The possible mechanism for this phenomenon is discussed in this report. CONCLUSION: This case illustrates two rather uncommon associations of a very common problem. Severe iron deficiency anemia may be associated with pancytopenia and iron replacement may cause a transient decline in megakaryopoiesis and leukopoiesis. Severe iron deficiency should be added to the list of conditions leading to thrombocytopenia.