Seunggu J. Han

Phase III Trial Comparing Whole-Pelvic Versus Prostate-Only Radiotherapy and Neoadjuvant Versus Adjuvant Combined Androgen Suppression: Radiation Therapy Oncology Group 9413

PURPOSE This trial tested the hypothesis that combined androgen suppression (CAS) and whole-pelvic (WP) radiotherapy (RT) followed by a boost to the prostate improves progression-free survival (PFS) by 10% compared with CAS and prostate-only (PO) RT. This trial also tested the hypothesis that neoadjuvant and concurrent hormonal therapy (NCHT) improves PFS compared with adjuvant hormonal therapy (AHT) by 10%. MATERIALS AND METHODS Eligibility included localized prostate cancer with an elevated prostate-specific antigen (PSA) < or = 100 ng/mL and an estimated risk of lymph node (LN) involvement of 15%. Between April 1, 1995, and June 1, 1999, 1,323 patients were accrued. Patients were randomly assigned to WP + NCHT, PO + NCHT, WP + AHT, or PO + AHT. Failure for PFS was defined as the first occurrence of local, regional, or distant disease; PSA failure; or death for any cause. RESULTS With a median follow-up of 59.5 months, WP RT was associated with a 4-year PFS of 54% compared with 47% in patients treated with PO RT (P =.022). Patients treated with NCHT experienced a 4-year PFS of 52% versus 49% for AHT (P =.56). When comparing all four arms, there was a progression-free difference among WP RT + NCHT, PO RT + NCHT, WP RT + AHT, and PO RT + AHT (60% v 44% v 49% v 50%, respectively; P =.008). No survival advantage has yet been seen. CONCLUSION WP RT + NCHT improves PFS compared with PO RT and NCHT or PO RT and AHT, and compared with WP RT + AHT in patients with a risk of LN involvement of 15%.

The role of microglia in central nervous system immunity and glioma immunology

The central nervous system (CNS) historically has been considered an immune-privileged organ, lacking a lymphatic system and shielded from the circulatory system by the blood-brain barrier. Microglia are an abundant portion of the CNS cell population, comprising 5% to 20% of the total glial cell population, and are as numerous as neurons. A crucial function of microglia is the ability to generate significant innate and adaptive immune responses. Microglia are involved in first line innate immunity of the CNS. Proper antigen presentation is critical in the generation of specific, durable responses by the adaptive immune system, and requires interaction between the T cell receptor and processed antigen peptide presented on major histocompatibility complex (MHC) molecules by the antigen presenting cells (APC). Microglia also have a large regulatory role in CNS immunity. Histopathologic studies of glioma tissue have consistently shown high levels of infiltrating microglia. Microglia are also localized diffusely throughout the tumor, rather than to the areas of necrosis, and phagocytosis of glioma cells or debris by microglia is not observed. Recent evidence indicates that glioma-infiltrating microglia/macrophages might be promoting tumor growth by facilitating immunosuppression of the tumor microenvironment. When activated, microglia can be potent immune effector cells, able to perform a broad range of functions, and they mediate both innate and adaptive responses during CNS injury and disease while remaining quiescent in the steady state. Their versatility in bridging the gap between the immune-privileged CNS and the peripheral immune system, in addition to their significant numbers in gliomas, makes them an attractive candidate in immunotherapy for gliomas. An enhanced understanding of microglia-glioma interaction may provide better methods to manipulate the glioma microenvironment to allow the generation of a specific and durable anti-glioma immunity. The role of microglia in CNS immunity is reviewed, with a focus on key advances made in glioma immunology.

Impact of extent of resection for recurrent glioblastoma on overall survival: clinical article.

OBJECT Extent of resection (EOR) has been shown to be an important prognostic factor for survival in patients undergoing initial resection of glioblastoma (GBM), but the significance of EOR at repeat craniotomy for recurrence remains unclear. In this study the authors investigate the impact of EOR at initial and repeat resection of GBM on overall survival. METHODS Medical records were reviewed for all patients undergoing craniotomy for GBM at the University of California San Francisco Medical Center from January 1, 2005, through August 15, 2009. Patients who had a second craniotomy for pathologically confirmed recurrence following radiation and chemotherapy were evaluated. Volumetric EOR was measured and classified as gross-total resection (GTR, > 95% by volume) or subtotal resection (STR, ≤ 95% by volume) after independent radiological review. Overall survival was compared between groups using univariate and multivariate analysis accounting for known prognostic factors, including age, eloquent location, Karnofsky Performance Status (KPS), and adjuvant therapies. RESULTS Multiple resections were performed in 107 patients. Fifty-two patients had initial GTR, of whom 31 (60%) had GTR at recurrence, with a median survival of 20.4 months (standard error [SE] 1.0 months), and 21 (40%) had STR at recurrence, with a median survival of 18.4 months (SE 0.5 months) (difference not statistically significant). Initial STR was performed in 55 patients, of whom 26 (47%) had GTR at recurrence, with a median survival of 19.0 months (SE 1.2 months), and 29 (53%) had STR, with a median survival of 15.9 months (SE 1.2 months) (p = 0.004). A Cox proportional hazards model was constructed demonstrating that age (HR 1.03, p = 0.004), KPS score at recurrence (HR 2.4, p = 0.02), and EOR at repeat resection (HR 0.62, p = 0.02) were independent predictors of survival. Extent of initial resection was not a statistically significant factor (p = 0.13) when repeat EOR was included in the model, suggesting that GTR at second craniotomy could overcome the effect of an initial STR. CONCLUSIONS Extent of resection at recurrence is an important predictor of overall survival. If GTR is achieved at recurrence, overall survival is maximized regardless of initial EOR, suggesting that patients with initial STR may benefit from surgery with a GTR at recurrence.

TGF-β downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients

The activating receptor NKG2D, expressed by natural killer (NK) cells and CD8(+) T cells, has a role in the specific killing of transformed cells. We examined NKG2D expression in patients with glioblastoma multiforme and found that NKG2D was downregulated on NK cells and CD8(+) T cells. Expression of NKG2D on lymphocytes significantly increased following tumor resection and correlated with an increased ability to kill NKG2D ligand-positive tumor targets. Despite the presence of soluble NKG2D ligands in the sera of glioblastoma patients, NKG2D downregulation was primarily caused by tumor-derived tumor growth factor-beta, suggesting that blocking of this cytokine may have therapeutic benefit.

Extent of surgical resection predicts seizure freedom in low-grade temporal lobe brain tumors

BACKGROUND: Achieving seizure control in patients with low-grade temporal lobe gliomas or glioneuronal tumors remains highly underappreciated, because seizures are the most frequent presenting symptom and significantly impact patient quality-of-life. OBJECTIVE: To assess how the extent of temporal lobe resection influences seizure outcome. METHODS: We performed a quantitative, comprehensive systematic literature review of seizure control outcomes in 1181 patients with epilepsy across 41 studies after surgical resection of low-grade temporal lobe gliomas and glioneuronal tumors. We measured seizure-freedom rates after subtotal resection vs gross-total lesionectomy alone vs tailored resection, including gross-total lesionectomy with hippocampectomy and/or anterior temporal lobe corticectomy. RESULTS: Included studies were observational case series, and no randomized, controlled trials were identified. Although only 43% of patients were seizure-free after subtotal tumor resection, 79% of individuals were seizure-free after gross-total lesionectomy (OR = 5.00, 95% confidence interval [CI]: 3.33-7.14). Furthermore, tailored resection with hippocampectomy plus corticectomy conferred additional benefit over gross-total lesionectomy alone, with 87% of patients achieving seizure freedom (OR = 1.82, 95% CI: 1.23-2.70). Overall, extended resection with hippocampectomy and/or corticectomy over gross-total lesionectomy alone significantly predicted seizure freedom (OR = 1.18, 95% CI: 1.11-1.26). Age <18 years and mesial temporal location also prognosticated favorable seizure outcome. CONCLUSION: Gross-total lesionectomy of low-grade temporal lobe tumors results in significantly improved seizure control over subtotal resection. Additional tailored resection including the hippocampus and/or adjacent cortex may further improve seizure control, suggesting dual pathology may sometimes allow continued seizures after lesional excision.

Individual Patient-Specific Immunity against High-Grade Glioma after Vaccination with Autologous Tumor Derived Peptides Bound to the 96 KD Chaperone Protein

Purpose: Cancer immunotherapy offers hope of a highly specific nontoxic adjuvant treatment. Heat shock protein peptide complexes (HSPPCs) found in cancer cells carry tumor-specific antigenic proteins and can facilitate adaptive and innate immune responses. Here we show that peptides bound to a 96 kD chaperone protein (HSP-96) from brain tissue containing glioblastoma multiforme (GBM) can be used to safely immunize patients with recurrent GBM. Experimental Design: Multimodality immunomonitoring was completed on 12 patients with recurrent GBM before and after immunization with an autologous HSPPC vaccine derived from surgically resected tumor. Clinical endpoints included safety assessments and overall survival. Results: No adverse events attributable to the vaccine were found. Testing of peripheral blood leukocytes before and after vaccination revealed a significant peripheral immune response specific for the peptides bound to HSP-96, in 11 of the 12 patients treated. Brain biopsies of immune responders after vaccination revealed focal CD4, CD8, and CD56 IFNγ positive cell infiltrates, consistent with tumor site specific immune responses. Immune responders had a median survival of 47 weeks after surgery and vaccination, compared with 16 weeks for the single nonresponder. Conclusions: These data provide the first evidence in humans of individual patient-specific immune responses against autologous tumor derived peptides bound to HSP-96. Clin Cancer Res; 19(1); 205–14. ©2012 AACR.

Hearing preservation after stereotactic radiosurgery for vestibular schwannoma: A systematic review

Radiosurgery has evolved into an effective alternative to microsurgical resection in the treatment of patients with vestibular schwannoma. We performed a systematic analysis of the literature in English on the radiosurgical treatment of vestibular schwannoma patients. A total of 254 published studies reported assessable and quantifiable outcome data of patients undergoing radiosurgery for vestibular schwannomas. American Association of Otolaryngology-Head and Neck Surgery (AAO-HNS) class A or B and Gardner-Robertson (GR) classification I or II were defined as having preserved hearing. A total of 5825 patients (74 articles) met our inclusion criteria. Practitioners who delivered an average dose of 12.5 Gy as the marginal dose reported having a higher hearing preservation rate (12.5 Gy=59% vs. >12.5 Gy=53%, p=0.0285). Age of the patient was not a significant prognostic factor for hearing preservation rates (<65 years=58% vs. >65 years=62%; p=0.4317). The average overall follow-up was 41.2 months. Our data suggest that an overall hearing preservation rate of about 57% can be expected after radiosurgical treatment, and patients treated with 12.5 Gy were more likely to have preserved hearing.

Complications and perioperative factors associated with learning the technique of minimally invasive transforaminal lumbar interbody fusion (TLIF)

Before the advent of minimally invasive spine surgery (MIS), open transforaminal lumbar interbody fusion (TLIF) was performed to treat spondylosis, spondylolisthesis, and spondylolysis. Minimally invasive TLIF has recently become more popular based upon the premise that a smaller, less traumatic incision should afford better recovery and outcomes. However, the learning curve associated with this technique must be considered. To analyze the perioperative factors associated with the learning curve in patients who underwent MIS TLIF versus open TLIF, we identified 22 patients who underwent TLIF from 2005 to 2008 within levels L4-S1 by the senior author (D.C.). Patients were subdivided into two groups according to whether they underwent: (i) MIS TLIF (10 patients, the first MIS TLIF procedures performed by D.C.); or (ii) open TLIF (12 patients). Preoperative, perioperative and postoperative factors were evaluated. Patients who underwent MIS TLIF had a statistically significant lower intraoperative transfusion rate, and rate of required postoperative surgical drains; and shorter periods of required drainage, and time to ambulation. However, the MIS TLIF group tended to have a higher rate of complications, which might have been associated with the learning curve. Both groups had a minimum of 1-year follow-up.

Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy

In patients with glioma, the tumor microenvironment can significantly impact pro-inflammatory immune cell functions. However, the mechanisms by which this occurs are poorly defined. Because immunosuppressive regulatory T cells (Treg) are over represented in the tumor microenvironment compared with peripheral blood, we hypothesized that the tumor may have an effect on Treg survival, migration, expansion, and/or induction of a regulatory phenotype from non-Treg conventional CD4+ T cells. We defined the impact of soluble factors produced by tumor cells on Treg from healthy patients in vitro to determine mechanisms by which gliomas influence T cell populations. We found that tumor-derived soluble factors allowed for preferential proliferation and increased chemotaxis of Treg, compared with conventional T cells, indicating that these mechanisms may contribute to the increased Treg in the tumor microenvironment. Conventional T cells also exhibited a significantly increased expression of pro-apoptotic transcripts in the presence of tumor-derived factors, indicating that survival of Treg in the tumor site is driven by exposure to soluble factors produced by the tumor. Together, these data suggest that tumor burden may induce increased Treg infiltration, proliferation, and survival, negating productive anti-tumor immune responses in patients treated with immunotherapies. Collectively, our data indicate that several mechanisms of Treg recruitment and retention in the tumor microenvironment exist and may need to be addressed to improve the specificity of immunotherapies seeking to eliminate Treg in patients with glioma.

CD8+ T-Cell Infiltrate in Newly Diagnosed Glioblastoma is Associated with Long-Term Survival

A growing body of evidence supports the significant interplay between the immune system and glioma pathogenesis. Here we investigate whether the extent of local glioma-associated CD8+ T-cell infiltrate at initial presentation correlates with long-term survival in patients with glioblastoma multiforme (GBM). The study was conducted by the University of California San Francisco Brain Tumor Research Center as part of the San Francisco Bay Area Adult Glioma Study, which included over 519 patients with GBM. A central neuropathology review was performed and populations of infiltrating CD8+ T-cells were quantified histologically. Of 108 patients studied, 43 patients had poor survival (<95days) and 65 patients had extended long-term survival of >403days. Tumors from long-term survivors were more likely than short-term survivors to have intermediate or extensive T-cell infiltrates compared to focal or rare infiltrates, and this association appears to be most significant in Caucasian women (p < 0.006). Thus, CD8+ T-cell infiltrate is associated with prolonged survival. Our data provide the impetus for more sophisticated studies to further elucidate prospectively the specific T-cell subtypes associated with long-term survival.