Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy.

BACKGROUND: The effect of immunologic and targeted agents on intracranial response rates in patients with melanoma brain metastases (MBMs) is not yet clearly understood. This report analyzes outcomes of intact MBMs treated with single-session stereotactic radiosurgery (SRS) and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors(i), BRAFi, or conventional chemotherapy. PATIENTS AND METHODS: Patients were included if MBMs were treated with single-session SRS within 3 months of receiving systemic therapy. The primary end point of this study was distant MBM control. Secondary end points were local MBM control defined as a >20% volume increase on follow-up MRI, systemic progression-free survival, overall survival (OS) from both SRS and cranial metastases diagnosis, and neurotoxicity. Images were reviewed alongside two neuro-radiologists at our institution. RESULTS: Ninety-six patients were treated to 314 MBMs over 119 SRS treatment sessions between January 2007 and August 2015. No significant differences were noted in age (P = 0.27), gender (P = 0.85), treated gross tumor volume (P = 0.26), or the diagnosis-specific graded prognostic assessment (P = 0.51) between the treatment cohorts. Twelve-month Kaplan-Meier (KM) distant MBM control rates were 38%, 21%, 20%, 8%, and 5% (P = 0.008) for SRS with anti-PD-1 therapies, anti-CTLA-4 therapy, BRAF/MEKi, BRAFi, and conventional chemotherapy, respectively. No significant differences were noted in the KM local MBM control rates among treatment groups (P = 0.25). Treatment with anti-PD-1 therapy, anti-CTLA-4 therapy, or BRAF/MEKi significantly improved OS on both univariate and multivariate analyses when compared with conventional chemotherapy. CONCLUSION: In our institutional analysis of patients treated with SRS and various systemic immunologic and targeted melanoma agents, significant differences in distant MBM control and OS are noted. Prospective evaluation of the potential synergistic effect between these agents and SRS is warranted.

Attenuated reovirus displays oncolysis with reduced host toxicity.

BACKGROUND: Although the naturally occurring reovirus causes only mild symptoms in humans, it shows considerable potential as an oncolytic agent because of its innate ability to target cancer cells. In immunocompromised hosts, however, wild-type reovirus can target healthy tissues, including heart, liver, pancreas and neural structures. METHODS: We characterized an attenuated form of reovirus (AV) derived from a persistently infected cell line through sequence analysis, as well as western blot and in vitro transcription and translation techniques. To examine its pathogenesis and oncolytic potential, AV reovirus was tested on healthy embryonic stem cells, various non-transformed and transformed cell lines, and in severe combined immunodeficiency (SCID) mice with tumour xenografts. RESULTS: Sequence analysis of AV reovirus revealed a premature STOP codon in its sigma 1 attachment protein. Western blot and in vitro translation confirmed the presence of a truncated σ1. In comparison to wild-type reovirus, AV reovirus did not kill healthy stem cells or induce black tail formation in SCID mice. However, it did retain its ability to target cancer cells and reduce tumour size. CONCLUSION: Despite containing a truncated attachment protein, AV reovirus still preferentially targets cancer cells, and compared with wild-type reovirus it shows reduced toxicity when administered to immunodeficient hosts, suggesting the potential use of AV reovirus in combination cancer therapy.

Reovirus therapy of tumors with activated Ras pathway.

Human reovirus requires an activated Ras signaling pathway for infection of cultured cells. To investigate whether this property can be exploited for cancer therapy, severe combined immune deficient mice bearing tumors established from v-erbB-transformed murine NIH 3T3 cells or human U87 glioblastoma cells were treated with the virus. A single intratumoral injection of virus resulted in regression of tumors in 65 to 80 percent of the mice. Treatment of immune-competent C3H mice bearing tumors established from ras-transformed C3H-10T1/2 cells also resulted in tumor regression, although a series of injections were required. These results suggest that, with further work, reovirus may have applicability in the treatment of cancer.

Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells.

Reovirus shows considerable potential as an oncolytic agent for Ras-activated tumors and is currently in clinical trials. Here we ask whether such tumor cell lines can acquire resistance to reoviral oncolysis. We challenged human HT1080 fibrosarcoma cells that carry a Ras mutation by prolonged exposure to reovirus, thereby yielding highly virus-resistant HTR1 cells. These cells are persistently infected with reovirus, exhibit high Ras activity and retain the original Ras gene mutation, showing that resistance to reovirus can be displayed in cells with active Ras. The HTR1 cells also exhibit reduced cellular cathepsin B activity, which normally contributes to viral entry and activation. Persistently infected HTR1 cells were not tumorigenic in vivo, whereas immunologically cured virus-free HTR1 cells were highly tumorigenic. Thus, acquisition of resistance to reovirus may constrain therapeutic strategies. To determine whether reoviral resistance is associated with a general reduction in apoptotic potential, we challenged the HTR1 cells with apoptotic inducers and E1B-defective adenovirus, resulting in significant apoptosis and cell death following both approaches. Therefore, even if resistance to reoviral oncolysis should arise in tumor cells in vivo, other therapeutic strategies may nevertheless remain effective.

Reovirus decreases azoxymethane-induced aberrant crypt foci and colon cancer in a rodent model.

Reovirus type 3 Dearing has demonstrated oncolytic efficacy in vitro and in vivo against a variety of cancer cell lines, tumor xenografts and syngeneic cancer models. In this study, we investigated the effectiveness of reovirus against aberrant crypt foci (ACF) and colon cancer induced by the carcinogen azoxymethane (AOM) in an immunocompetent rat model. Sprague-Dawley rats received 15 mg/kg AOM intraperitoneally once per week for 4 weeks and reovirus was administered rectally once a week for 5 weeks starting 20 weeks after the last dose of AOM. Two weeks after completion of reovirus therapy, animals were examined for tumor burden in the colon and other tissues. Reovirus-treated animals showed a decrease in total ACF numbers (P=0.014), in large ACFs (P=0.0069) and in tumor number (P=0.03) compared to vehicle-treated animals. Fewer obstructing tumors in the colon (P=0.07) and duodenum (P=0.03) and reduced hepatic metastases were also noted. In addition, a tumor cell line derived from hepatic metastases was found to be susceptible to reovirus in vitro. Our results show that repeated rectal reovirus administration had some efficacy in the treatment and prevention of AOM-induced ACFs, colon cancers and metastases.

Matrix metalloproteinases and diseases of the CNS.

Matrix metalloproteinases (MMPs) are increasingly being implicated in the pathogenesis of several CNS diseases. In multiple sclerosis, MMPs could be responsible for the influx of inflammatory mononuclear cells into the CNS, contribute to myelin destruction and disrupt the integrity of the blood-brain barrier; in Alzheimer's disease, MMPs might mediate the deposition of amyloid beta-proteins; and MMPs are known to contribute to the invasiveness of malignant glioma cells and might regulate their angiogenic capacity. Nonetheless, MMPs could also have beneficial roles in recovery from CNS injury.Therefore, both the identity of the MMP and its cellular origin could determine whether disease pathogenesis or regeneration occurs, and thus synthetic MMP inhibitors might be valuable for treating some CNS diseases.

Reovirus as an oncolytic agent against experimental human malignant gliomas.

BACKGROUND: Reovirus is a naturally occurring oncolytic virus that usurps activated Ras-signaling pathways of tumor cells for its replication. Ras pathways are activated in most malignant gliomas via upstream signaling by receptor tyrosine kinases. The purpose of this study was to determine the effectiveness of reovirus as an experimental treatment for malignant gliomas. METHODS: We investigated whether reovirus would infect and lyse human glioma cell lines in vitro. We also tested the effect of injecting live reovirus in vivo on human gliomas grown subcutaneously or orthotopically (i.e., intracerebrally) in mice. Finally, reovirus was tested ex vivo against low-passage cell lines derived from human glioma specimens. All P values were two-sided. RESULTS: Reovirus killed 20 (83%) of 24 established malignant glioma cell lines tested. It caused a dramatic and often complete tumor regression in vivo in two subcutaneous (P =.0002 for both U251N and U87) and in two intracerebral (P =.0004 for U251N and P =.0009 for U87) human malignant glioma mouse models. As expected, serious toxic effects were found in these severely immunocompromised hosts. In a less immunocompromised mouse model, a single intratumoral inoculation of live reovirus led to a dramatic prolongation of survival (compared with control mice treated with dead virus; log-rank test, P<.0001 for both U251N and U87 cell lines). The animals treated with live virus also appeared to be healthier and gained body weight (P =.0001). We then tested the ability of reovirus to infect and kill primary cultures of brain tumors removed from patients and found that it killed nine (100%) of nine glioma specimens but none of the cultured meningiomas. CONCLUSIONS: Reovirus has potent activity against human malignant gliomas in vitro, in vivo, and ex vivo. Oncolysis with reovirus may be a potentially useful treatment for a broad range of human cancers.

Phase transition in charged lipid membranes.

Experimental results on the effect of electrostatics on bilayer phase transitions are compared with corresponding data for monolayers and the predictions of electrical double layer theory. The two substantial conclusions which emerge are that: (i) double layer theory based on a continuous surface charge distribution cannot explain all the relevant data, a situation which may be improved by taking into account the discrete nature of the surface charge distribution; (ii) the crystal - liquid crystal phase transition of charged bilayer membranes is always a continuous one which takes place through an intermediate state consisting of both fluid and frozen domains.

Prospective study of postoperative magnetic resonance imaging in patients with malignant gliomas.

PURPOSE: We studied the natural history of postoperative enhancement on magnetic resonance (MR) scans in patients with malignant glioma to determine the following: (1) when a postoperative MR scan most accurately shows residual enhancing tumor; and (2) whether repeated doses of the contrast agent gadopentetate dimeglumine (Gd-DTPA) were well tolerated. PATIENTS AND METHODS: Seventeen patients with malignant glioma underwent tumor resection; four (24%) had nonenhancing tumors preoperatively. Serial MR scans were performed on postoperative days 1, 3, 5, 7, 14, and 21 and were analyzed qualitatively and quantitatively. The evolution of enhancement and subacute hemorrhage were described and measured. A uniform schedule of postoperative dexamethasone administration was used in all but four patients (24%) (each required higher doses to maintain neurologic function). RESULTS: Nontumoral, marginal (i.e., postsurgical) enhancement, potentially mimicking residual tumor, developed in eight patients (53%), including tumors that were nonenhancing preoperatively, and was maximal from days 5 to 14. Tumor enhancement was optimally visualized on postoperative days 3 to 5. Nine of 10 patients (90%) with gross residual enhancing tumor showed an increase of enhancing tumor size during the study. Methemoglobin was detected at some time in all patients (100%) and was usually minor, but in six (35%) it interfered with residual tumor assessment. The 97 doses of Gd-DTPA, administered in 17 patients, were well tolerated. CONCLUSION: When accurate assessment of residual enhancing tumor is needed in patients with malignant glioma, an MR scan performed on postoperative days 3 to 5 should minimize the confounding effects of postsurgical enhancement and methemoglobin. The repeated administration of Gd-DTPA over several weeks is well tolerated.

Cellular proliferation in pilocytic and diffuse astrocytomas.

Using quantitative image analysis, we evaluated the MIB-1 labeling index (LI) in a large population of pilocytic (n = 131) and diffuse astrocytomas (n = 140), explored its significance as a prognostic predictor of survival, and compared it to other commonly accepted predictors, including grade and its histologic determinants, atypia, mitoses, endothelial proliferation, and necrosis. Diffuse astrocytomas were graded according to the St Anne-Mayo scheme and included 45 grade 2, 50 grade 3, and 45 grade 4 astrocytomas. In pilocytic astrocytomas, mean, median, and range of MIB-1 LIs were 1.1, 0.9, and 0-3.9%, respectively. In diffuse astrocytomas, these values were 2.3, 2, and 0-7.6% in grade 2; 6, 4.4, and 0.1-25.7% in grade 3; 9.1, 6, and 0.3-36% in grade 4. There was a significant difference in the distribution of MIB-1 LIs between pilocytic and diffuse grade 2 astrocytomas (p < 0.001), between grade 2 and grade 3 (p < 0.001), and between tumors of grade 3 and 4 (p = 0.014). Among pilocytic astrocytomas there was no association between survival and MIB-1 LI or any histologic parameter. In diffuse astrocytomas, MIB-1 LI was significantly correlated with grade as well as with mitotic activity (<0.001) and survival. While in diffuse astrocytomas of all grades, necrosis was the strongest factor associated with survival, in tumors of grades 2 and 3 the MIB-1 LI preceded other histologic parameters and, on multivariate analysis, remained the only feature predictive of survival. Grade 3 astrocytomas with a single "solitary" mitosis had a significantly lower MIB-I LI than did grade 3 tumors with >1 mitosis and, compared to the latter, had a significantly longer survival (p = 0.013), one not significantly different from patients with grade 2 astrocytomas. These findings suggest that the cutoff point between grade 2 and 3 in the St. Anne-Mayo scheme may not be optimal and may need to be revised.

Localization of gelatinase-A and gelatinase-B mRNA and protein in human gliomas.

Malignant gliomas maintain a poor prognosis and survival rate due to their marked local invasive growth and neovascularization. Matrix metalloproteinases (MMPs) have been implicated in glioma invasion and angiogenesis, but it is unknown whether they are produced by the tumor cells or surrounding stroma. Using in situ hybridization and immunohistochemistry, we found expression of mRNA for both gelatinase-A (MMP2) and gelatinase-B (MMP9) localized to tumor cells and vascular structures in glioma sections. Gelatinase-A protein expression was detected most prominently in tumor cells, with very little signal seen in vasculature. Gelatinase-B protein expression was prominent in vascular structures but was also expressed in tumor cells. Our data show that these proteases are produced by glioma cells and vascular structures and suggest that synthetic MMP inhibitors might be useful in this disease.

Headaches in patients with brain tumors: a study of 111 patients.

We examined 111 consecutive patients with primary or metastatic brain tumors identified by CT or MRI to characterize brain tumor headache. The median age was 44 years; 34% had primary and 66% metastatic tumors. Headaches were present in 48%, equally for primary and metastatic brain tumors. Headaches were similar to tension-type in 77%, migraine-type in 9%, and other types in 14%. The typical headache was bifrontal but worse ipsilaterally, and was the worst symptom in only 45% of patients. Unlike true tension-type headaches, brain tumor headaches were worse with bending over in 32%, and nausea or vomiting was present in 40% of patients. The "classic" early morning brain tumor headache is uncommon. Nausea, vomiting, an abnormal neurologic examination, or a significant, change in prior headache pattern suggest that the headache may be caused by a tumor.

Combined-modality therapy in the treatment of primary central nervous system lymphoma in AIDS.

PURPOSE: Conventional therapy--ie, treatment with corticosteroids and cranial radiotherapy (RT)--is inadequate to treat AIDS-related primary central nervous system lymphoma (PCNSL), as it achieves a median survival of only 2 to 5 months. Chemotherapy added to RT in non-AIDS PCNSL improves disease control and prolongs survival. We studied the efficacy of this approach with RT in AIDS-related PCNSL. METHODS: Ten AIDS patients with PCNSL were treated with chemotherapy--nine at diagnosis and one at recurrence. None had evidence of systemic lymphoma. All patients treated at diagnosis received pre-RT methotrexate--eight also received thiotepa and procarbazine--followed by whole-brain RT. The patient treated at recurrence (who had been previously irradiated) received chemotherapy alone, including methotrexate, thiotepa, and procarbazine. RESULTS: All had enhancing lesions on MRI and five (50%) had a single lesion (seven [70%] had a ring-enhancing mass). No patient had a response to corticosteroids. Four of seven (57%) assessable patients had a partial or complete response to chemotherapy prior to RT. Six of seven (86%) assessable patients had a complete response at the end of treatment. Median survival was 3.5 months for all 10 patients and 7 months for the eight patients who completed therapy. Two patients survived for 1 year or longer. Eight patients died--six from infection (two treatment-related), one from progressive dementia, and one from a gastrointestinal hemorrhage. CONCLUSION: AIDS-related PCNSL responds to chemotherapy and RT, but only a few patients benefit with prolonged survival.

Malignant supratentorial glioma in the elderly: is radiotherapy useful?

OBJECTIVES: To determine (1) if radiotherapy (RT) improves survival or neurologic function in elderly patients with malignant supratentorial glioma (MSG) and (2) which prognostic factors predict survival. BACKGROUND: The prevalence of MSG is increasing because both the number of elderly patients and the age-adjusted incidence are increasing. Because age is a powerful negative prognostic factor in MSG, it is not clear if RT is useful in the elderly. DESIGN/METHODS: We retrospectively studied 103 patients from the Southern Alberta Cancer Registry diagnosed January 1, 1978, to December 31, 1993, aged 70 yrs, with MSG in whom sufficient clinical and follow-up information was available. Multiple treatment and patient factors were compared with survival and neurologic function score. Diagnosis was confirmed in 15 (14.6%) by biopsy, in 66 (64.1%) by resection, and in 22 (21.4%) by clinical course and typical radiographic appearance only. RESULTS: All patients died and median survival was 3.9 months. Better neurologic function at diagnosis and administration of RT were independently associated with significantly longer survivals (p = 0.001 and < 0.001; log rank test). However, RT was only associated with longer survival in patients aged less than 80 years. Neurologic status only rarely improved following RT. CONCLUSIONS: The prognosis for elderly patients with MSG is poor. RT is unlikely to benefit patients who are aged 80 years or older. RT has a short-lived benefit for patients who are functionally disabled.

How often are nonenhancing supratentorial gliomas malignant? A population study.

The presence of contrast enhancement in a brain tumor is often regarded as a sign of malignancy. The authors identified 314 patients with malignant and low-grade supratentorial glial neoplasms in an unselected population, 58 of which lacked contrast enhancement on preoperative neuroimaging. Nonenhancing gliomas were malignant in approximately one third of cases, especially in older patients. Histologic confirmation of the diagnosis is therefore important in all patients suspected of harboring a primary glial neoplasm.

Biology and management of AIDS-associated primary CNS lymphomas.

Primary central nervous system (CNS) lymphoma is the most common brain tumor in patients with AIDS and occurs in about 10% of this population. CT/MR scan usually demonstrates single or multiple contrast enhancing masses that are radiographically indistinguishable from other CNS processes such as toxoplasmosis. Brain biopsy, positive cerebrospinal fluid (CSF) cytology, or possibly the demonstration of Epstein-Barr viral DNA in the CSF can establish the diagnosis. Cranial radiotherapy (RT) has been the cornerstone of therapy and produces responses in most patients, but their median survival is still only a few months. The addition of chemotherapy to RT may prolong survival in a sub-group of patients.

Lymph node metastases from glioblastoma multiforme.

Extraneural metastases from glioblastoma multiforme are rare. Spread to the extracranial head and neck may be evident on routine follow-up images of the original lesion. We present two cases, one with documented metastatic adenopathy in the head and neck from glioblastoma and the other with probable metastatic disease in a lymph node in which biopsy was not performed, and discuss probable mechanisms of extraneural extension of this tumor.

Intracranial chordomas: a clinicopathological and prognostic study of 51 cases.

Fifty-one patients with intracranial chordomas who were surgically treated between 1960 and 1984 were studied. Median patient age was 46 years, and 73% presented with diplopia or headache. Nineteen tumors were classified as the "chondroid" type. The extent of surgical removal was a biopsy in 11 patients and subtotal removal or greater in 40. Thirty-nine patients received postoperative radiation therapy. At the time of analysis, 17 patients were alive, and the estimated 5- and 10-year survival rates were 51% and 35%, respectively, for the group of 51 patients. Univariate analysis showed that: 1) patients undergoing resection lived longer (the 5-year survival rate was 36% for the 11 biopsy patients compared with 55% for the 40 patients who had resection; 2) patients who underwent postoperative radiotherapy tended to have longer disease-free survival times; and 3) overall and disease-free survival data were the same for patients with chondroid tumors and those with typical chordomas. Multivariate analysis showed that: 1) age was the factor most strongly associated with longer overall and disease-free survival; 2) diplopia was associated with longer survival; and 3) tumoral mitotic activity tended to be associated with shorter disease-free survival. One tumor metastasized to the cervical cord, and two tumors underwent anaplastic transformation. These data suggest that the prognosis in patients with chordomas is unfavorable, young age is the single factor most strongly associated with longer survival, surgical resection is beneficial, and postoperative radiotherapy may prolong disease-free survival.

Radiation necrosis or glioma recurrence: is computer-assisted stereotactic biopsy useful?

Fifty-one patients with supratentorial glioma treated with external beam radiotherapy (median dose 59.5 Gy) who then demonstrated clinical or radiographic evidence of disease progression underwent stereotactic biopsy to differentiate tumor recurrence from radiation necrosis. The original tumor histological type was diffuse or fibrillary astrocytoma in 21 patients (41%), oligodendroglioma in 13 (26%), and oligoastrocytoma in 17 (33%); 40 tumors (78%) were low-grade (Kernohan Grade 1 or 2). The median time to suspected disease progression was 28 months. Stereotactic biopsy showed tumor recurrence in 30 patients (59%), radiation necrosis in three (6%), and a mixture of both in 17 (33%); one patient (2%) had a parenchymal radiation-induced chondroblastic osteosarcoma. The tumor type at stereotactic biopsy was similar to the original tumor type and was astrocytoma in 24 patients (47%), oligodendroglioma in eight (16%), oligoastrocytoma in 16 (31%), unclassifiable in two (4%), and chondroblastic osteosarcoma in one patient (2%). At biopsy, however, only 19 tumors (37%) were low grade (Kernohan Grade 1 or 2). Subsequent surgery confirmed the stereotactic biopsy histological findings in eight patients. Follow-up examination showed 14 patients alive with a median survival of 1 year for the entire group. Median survival times after biopsy were 0.83 year for patients with tumor recurrence and 1.86 years for patients with both tumor recurrence and radionecrosis; these findings were significantly different (p = 0.008, log-rank test). No patient with radiation necrosis alone died. Other factors associated with reduced survival were a high proportion of residual tumor (p = 0.024), a low proportion of radionecrosis (p < 0.001), and a Kernohan Grade of 3 or 4 (p = 0.005). In conclusion, in patients with previously irradiated supratentorial gliomas in whom radionecrosis or tumor recurrence was clinically or radiographically suspected, results of stereotactic biopsy could be used to differentiate tumor recurrence, radiation necrosis, a mixture of both lesions, or radiation-induced neoplasm. In addition, biopsy results could predict survival rates.

Role of oropharyngeal stimulation in cholecystokinin-induced satiety in the sham feeding rat.

The belief that oropharyngeal stimulation potentiates the satiety produced by cholecystokinin (CCK) is based on the demonstration that the ability of 20% pure CCK to suppress feeding is enhanced the closer it is injected to a meal. The increase efficacy of CCK with closer temporal proximity to a meal might simply reflect increased peptide levels at the time of feeding. Further, since oropharyngeal synergy has never been demonstrated with pure CCK, studies were performed to evaluate the role of oropharyngeal stimulation in CCK-induced satiety. Rats equipped with gastric fistulae were injected IP with CCK-8 15 min before a test sham feed. In one condition, rats sham fed for 15 min prior to CCK injection; in the other, they did not. CCK-8 suppressed eating in only those cases when its administration was accompanied by oropharyngeal stimulation. Thus, oropharyngeal cues enhance the satiety action of exogenous CCK. A second experiment examined whether oropharyngeal synergy requires oropharyngeal stimulation prior to peptide delivery. CCK-8 was injected into rats coincident with the initation of a test sham feed. Rats had either sham fed, or not sham fed, for 15 min prior to CCK administration. Both conditions produced similar and significant suppressions of eating during the test sham feed. Thus, oropharyngeal cues enhance the action of CCK and oropharyngeal amplification needs only contiguous pairings of oropharyngeal stimulation and feeding.