Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Role of surgery, radiotherapy and chemotherapy in papillary tumors of the pineal region: a multicenter study.

Papillary tumor of the pineal region (PTPR), recently described as a distinct clinicopathological entity, can show aggressive biological behavior. The optimal therapeutic approach of PTPR has not been well defined. The role of surgery, radiotherapy, and chemotherapy in the treatment of PTPR was analyzed in a large multicenter series. In order to determine factors that influence prognosis, outcome data of a series of 44 patients with histopathologically proven PTPR were retrospectively analyzed. Of the 44 patients, 32 were still alive after a median follow-up of 63.1 months. Twelve patients experienced progressive disease, with seven undergoing two relapses and five more than two. Median overall survival (OS) was not achieved. Median progression-free survival (PFS) was 58.1 months. Only gross total resection and younger age were associated with a longer OS, radiotherapy and chemotherapy having no significant impact. PFS was not influenced by gross total resection. Radiotherapy and chemotherapy had no significant effect. This retrospective series confirms the high risk of recurrence in PTPR and emphasizes the importance of gross total resection. However, our data provide no evidence for a role of adjuvant radiotherapy or chemotherapy in the treatment of PTPR.

Preoperative evaluation of the deep cerebral veins using 3-tesla magnetic resonance imaging.

BACKGROUND: Surgical treatment of deep-seated tumors such as supratentorial intraventricular and thalamic-pineal-tectal region tumors carries a risk of postoperative deficits due to possible damage to deep cerebral veins including the internal cerebral vein. It is often difficult to identify whether the vessel encountered during surgery needs to be preserved or not through the small operative field. Therefore, preoperative evaluation of deep venous structures is important. We evaluated the usefulness of 3-Tesla magnetic resonance imaging (3 T MRI) for this purpose. METHODS: First, the ability to detect deep venous structures was compared with both 3-dimensional computed tomographical angiography (3D-CTA) and 3 T MRI in patients without any damage to deep venous structures. Images of 7 consecutive patients suffering from insulo-opercular gliomas who underwent both imaging modes for the identification of lateral striate arteries were reconstructed for evaluation of the deep cerebral veins. Subsequently, surgery for tumors at the supratentorial intraventricular and thalamic-pineal-tectal regions was prospectively performed with preoperative evaluation of deep venous system only using 3 T MRI. RESULTS: Information on the deep venous systems acquired by 3 T MRI was as useful as that acquired by 3D-CTA. Until today, we have treated 8 cases of supratentorial intraventricular and thalamic-pineal-tectal region tumors with preoperative evaluation of the deep venous system using 3 T MRI without any morbidity. CONCLUSION: Information on the deep venous system obtained with 3 T MRI aids the surgery of supratentorial intraventricular and thalamic-pineal-tectal region tumors. As the required sequences of 3 T MRI are same as those necessary for the neuronavigation system, and 3 T MRI can be achieved without the use of iodine-based contrast agents, 3 T MRI can be an alternative for preoperative evaluation of the deep venous systems.

Chlorination by-products of fenitrothion.

The mutagens produced through chemical reaction between chlorine and the insecticide fenitrothion were studied by using a quadrupole GC-MS. The mutagenicity and the mutagen formation potential (MFP) of the identified by-products were evaluated by the Ames assay (preincubation method) using Salmonella typhimurium TA100 without exogenous activation by S9 mix (TA100-S9). Before conducting GC/MS analyses, six compounds were presumed to be produced in chlorinated fenitrothion. These compounds were confirmed to be produced by the GC/MS analyses, but none of them were mutagenic. One of the chlorination by-products, 3-methyl-4-nitrophenol, has 19 times greater MFP than that of fenitrothion. This result suggests that a major mutagen in chlorinated fenitrothion will be produced via a chemical reaction between chlorine and 3-methyl-4-nitrophenol.

Virtually peeling off the skull and scalp: a simple way of mapping the superficial cerebral veins on the brain surface.

PURPOSE: A simple MRI postprocessing technique was developed to display superficial cerebral veins (SCVs) along with brain surface structures. MATERIALS AND METHODS: Thirty-one consecutive patients with brain tumors were studied. All patients underwent brain MR examination, from which three-dimensional (3D) images were reconstructed. Simulation images of craniotomy were created by cutting away the signal from the skull and scalp at the region corresponding to the window planned for surgery. Detectability of the SCVs was evaluated by comparing the simulation images with intraoperative photographs. Reasons for those undetectable SCVs on simulation images of craniotomy were discussed. RESULTS: Detectability of the SCVs >2 mm was 100%; those from 1 to 2 mm was 88.5%, and those from 0.5 to 1 mm 56.9%. Effacement of cortical sulci/subarachnoid space around the supposed craniotomy site, dural/meningeal contrast enhancement and insufficient spatial resolution of the source images were regarded as the main reasons for undetectable SCVs. CONCLUSION: Virtually peeling off the skull and scalp well demonstrates the SCVs along with brain surface structures. This simple technique can provide useful information about the SCVs and their relationships with cortical structures and tumors for preoperative surgical planning.

Primary CNS lymphoma treated with combined intra-arterial ACNU and radiotherapy.

OBJECT: To assess whether nimustine (ACNU), a drug that can cross the blood brain barrier, combined with radiotherapy, improved the survival of patients with primary central nervous system lymphoma (PCNSL). CLINICAL MATERIALS AND METHODS: Between 1995 and 2005, we treated 63 immunocompetent PCNSL patients with combination therapy consisting of intra-arterial ACNU (100 mg/m(2)) and whole brain radiotherapy (36-50 Gy). Their median age was 60 years (range 28-81). The median follow-up was 24 months. FINDINGS: With this regimen we achieved a complete response rate of 75% (43 of 57 patients). Kaplan-Meier estimates for median progression-free survival and median overall survival were 26 and 39 months, respectively. The 3- and 5-year survival rates were 51% (95% confidence interval [CI], 36-65%) and 32% (95% CI, 17-47%), respectively. By multivariate analysis, age (<60 vs. > or =60 years) was the only statistically significant prognostic factor; the WBRT dose, sex, and number of tumors were not significant prognostic factors in this study. Myelosuppression was the most frequent side effect, 60% of patients experienced grade 3-4 leukopenia. Late neurotoxicity as a result of treatment was observed in 14 of 43 patients (34%) and higher age (>60) was associated with a high risk of neurotoxicity. CONCLUSION: The intra-arterial administration of ACNU combined with radiation therapy yielded a high response rate at acceptable toxicity levels in younger patients with PCNSL. However, late neurotoxicity was a serious complication in patients above 60 years of age.

Time-of-Flight MR Angiography for Detection of Cerebral Hyperperfusion Syndrome after Superficial Temporal Artery-Middle Cerebral Artery Anastomosis in Moyamoya Disease.

BACKGROUND AND PURPOSE: Cerebral hyperperfusion syndrome is a potential complication of superficial temporal artery-MCA anastomosis for Moyamoya disease. In this study, we evaluated whether TOF-MRA could assess cerebral hyperperfusion syndrome after superficial temporal artery-MCA anastomosis for this disease. MATERIALS AND METHODS: This retrospective study included patients with Moyamoya disease who underwent superficial temporal artery-MCA single anastomosis. TOF-MRA and SPECT were performed before and 1-6 days after anastomosis. Bilateral ROIs on the source image of TOF-MRA were manually placed directly on the parietal branch of the superficial temporal artery just after branching the frontal branch of the superficial temporal artery and on the contralateral superficial temporal artery on the same axial image, respectively. The change ratio of the maximum signal intensity of the superficial temporal artery on TOF-MRA was calculated by using the following formula: (Postoperative Ipsilateral/Postoperative Contralateral)/(Preoperative Ipsilateral/Preoperative Contralateral). RESULTS: Of 23 patients (26 sides) who underwent the operation, 5 sides showed cerebral hyperperfusion syndrome postoperatively. There was a significant difference in the change ratio of signal intensity on TOF-MRA observed between the cerebral hyperperfusion syndrome and non-cerebral hyperperfusion syndrome groups (cerebral hyperperfusion syndrome group: 1.88 ± 0.32; non-cerebral hyperperfusion syndrome group: 1.03 ± 0.20; P = .0009). The minimum ratio value for the cerebral hyperperfusion syndrome group was 1.63, and the maximum ratio value for the non-cerebral hyperperfusion syndrome group was 1.30. Thus, no overlap was observed between the 2 groups for the change ratio of signal intensity on TOF-MRA. CONCLUSIONS: Diagnosis of cerebral hyperperfusion syndrome is indicated by an increase in the change ratio of signal intensity on TOF-MRA by more than approximately 1.5 times the preoperative levels.

Structural and functional evidence for the presence of tumor suppressor genes on the short arm of chromosome 10 in human gliomas.

Loss of heterozygosity (LOH) observed at polymorphic loci on both arms of chromosome 10 in many human gliomas suggests the presence of multiple tumor suppressor genes on this chromosome. Recently, the PTEN/MMAC1 gene on 10q23 was isolated as one of these putative glioma suppressors. To determine the subchromosomal localization of others, we analysed 79 gliomas for LOH using 30 polymorphic microsatellite markers on the short arm and 10 markers on the long arm of chromosome 10. Twenty tumors showed LOH at all the loci examined, while 17 others showed LOH at loci on a portion of chromosome 10. Deletion mapping of the latters demonstrated that two distinct regions, encompassing genetic distances of 5.6 cM on 10p15 and 5.5 cM on 10p14, were lost frequently. Introduction of chromosomal fragments 10p14-p15, which included the entire region on 10p15 and a portion of that on 10p14 assigned by deletion mapping, into the human glioblastoma cell line T98G through microcell-mediated chromosome transfer markedly suppressed colony forming ability in soft agar compared with parental T98G cells. The combined results of structural and functional analyses strongly suggest that aberrations of the tumor suppressor gene(s) within chromosomal region 10p14-p15 are involved in development of human gliomas.

Amplification of alpha-platelet-derived growth factor receptor gene lacking an exon coding for a portion of the extracellular region in a primary brain tumor of glial origin.

In a primary brain tumor of glial origin, we found overexpression of the alpha-platelet-derived growth factor (alpha-PDGF) receptor mRNA. Southern blot analysis of the gene revealed amplification of the rearranged alpha-PDGF receptor gene in the glioma. A cDNA coding for an aberrant transcript from the amplified receptor gene was obtained and characterized. Partial nucleotide sequence analysis of the cDNA revealed a deletion of 243 nucleotides coding for 81 amino acids in a portion of the immunoglobulin-like domains of the extracellular region of the receptor. cDNA polymerase chain reaction (PCR) of the total cellular RNA in the glioma indicated that more than 80% of the transcripts have a deletion of 243 nucleotides. Analysis of a PCR-amplified DNA fragment derived from the amplified alpha-PDGF receptor gene in the glioma revealed that an exon coding for the 81 amino acids was removed by a 2.1 kb gene deletion. We also found amplification of the alpha-PDGF receptor gene in macroscopically normal cortex adjacent to the glioma from the same patient. The amplified gene in the macroscopically normal cortex has no major gene deletion, suggesting that gene amplification is not sufficient for the development of malignant gliomas.

Microsatellite instability and the PTEN1 gene mutation in a subset of early onset gliomas carrying germline mutation or promoter methylation of the hMLH1 gene.

High-frequent microsatellite instability (MSI-H) was detected in two of the 80 gliomas examined, whlie the other 78 gliomas showed microsatellite stable (MSS) phenotype. Both of the two MSI-H tumors were glioblastomas which developed in teenage patients. One of the patient was diagnosed as having Turcot's syndrome and had a germline mutation in the hMLH1 gene. Loss of expression due to promoter methylation was selectively observed in the wild type allele of the hMLH1 gene in the tumor of this patient. The other patient had neither a family history nor a past personal history of malignancy. Although no mutation in the mismatch repair genes was detected in the tumor of this patient, the level of expression of the hMLH1 gene was markedly decreased and the promoter sequence of the gene was highly methylated. In the tumor of this patient, the PTEN1 gene, one of the genes carrying microsatellite sequences in their coding regions, was altered by a slippage mutation within five adenine repeat sequences. These findings indicate that the genetic or epigenentic inactivation of the hMLH1 gene is involved in a subset of early-onset gliomas and the PTEN1 gene could be a downstream target for mutation as observed in glioblastoma without MSI.

Fatty acid induced glioma cell growth is mediated by the acyl-CoA synthetase 5 gene located on chromosome 10q25.1-q25.2, a region frequently deleted in malignant gliomas.

Acyl-CoA synthetase (ACS) ligates fatty acid and CoA to produce acyl-CoA, an essential molecule in fatty acid metabolism and cell proliferation. ACS5 is a recently characterized ACS isozyme highly expressed in proliferating 3T3-L1 cells. Molecular characterization of the human ACS5 gene revealed that the gene is located on chromosome 10q25.1-q25.2, spans approximately 46 kb, comprises 21 exons and 22 introns, and encodes a 683 amino acid protein. Two major ACS5 transcripts of 2.5- and 3.7-kb are distributed in a wide range of tissues with the highest expression in uterus and spleen. Markedly increased levels of ACS5 transcripts were detected in a glioma line, A172 cells, and primary gliomas of grade IV malignancy, while ACS5 expression was found to be low in normal brain. Immunohistochemical analysis also revealed strong immunostaining with an anti-ACS5 antibody in glioblastomas. U87MG glioma cells infected with an adenovirus encoding ACS5 displayed induced cell growth on exposure to palmitate. Consistent with the induction of cell growth, the virus infected cells displayed induced uptake of palmitate. These results demonstrate a novel fatty acid-induced glioma cell growth mediated by ACS5.

Functional evaluation of p53 and PTEN gene mutations in gliomas.

We screened mutations of two major tumor suppressor genes, p53 and PTEN, in 66 human brain tumors using a yeast-based functional assay and cDNA-based direct sequencing, respectively. The frequency of p53 mutations was 28.8% (19 of 66) and was higher in anaplastic astrocytoma (9 of 14, 64.3%,) than in glioblastoma multiforme (GBM; 7 of 27, 25.9%,), supporting previous speculation that there are at least two genetic pathways leading to GBM, a de novo pathway without p53 mutation and a "progressive" pathway with p53 mutation. PTEN mutation was observed in 8 of 64 tumors (12.5%), mainly GBMs (7 of 26, 26.9%), both with and without p53 mutation. These results suggest that mutation of the PTEN gene is a later event than that of the p53 gene in glioma progression and is associated with both the genetic pathways. All of the detected PTEN missense mutations and an in-frame small deletion inactivated PTEN phosphoinositide phosphatase activity in vitro. Because the tumors containing PTEN mutations also showed loss of heterozygosity in the chromosome 10q23 region flanking the PTEN gene, our data clearly indicate that inactivation of both PTEN alleles occurs in a subset of high-grade gliomas, therefore confirming the previous idea that PTEN acts as a tumor suppressor gene.

Intraoperative localisation of the lip sensory area by somatosensory evoked potentials.

Accurate localisation of the central sulcus enables maximum tumour resection with minimum morbidity in peri-Rolandic surgery. We investigated intraoperative somatosensory evoked potentials (SSEPs) with combined recording of lower lip and median nerve stimuli during craniotomy in nine patients with peri-Rolandic glioma. Using a custom clip electrode, the lip mucous membrane was stimulated with biphasic pulses with 0.2 ms duration, 10-14 mA intensity and a frequency of 0.7 Hz. Polarity inversion of the SSEP was detected across the central sulcus using median nerve and/or lower lip stimulation in eight of the nine patients in whom the tumour did not infiltrate the lip or hand sensory area. Recording of SSEPs with lower lip stimulation is useful if the resection margin is planned lateral to the hand representation area, if the hand representation area is not exposed by the craniotomy, or if the SSEPs for median nerve stimulation are not clear due to tumour infiltration.

Correlation between choline level measured by proton MR spectroscopy and Ki-67 labeling index in gliomas.

BACKGROUND AND PURPOSE: The clinical relevance of proton MR spectroscopy needs further clarification as to its usefulness and limitations. The purpose of this study was to investigate the correlation between the semiquantitative choline-containing compound level (Cho value) measured by MR spectroscopy and the Ki-67 labeling index in gliomas. METHODS: Localized proton spectra were obtained in 26 consecutive patients with glioma who subsequently underwent surgery for tumor removal. Metabolic values in the spectra were measured semiquantitatively using an external standard of reference. The Ki-67 labeling index was measured in the surgical specimen. Because the semiquantitative metabolic values may be affected by tissue components included in the spectroscopic voxel, the MR imaging appearance of the voxel within the tumor was classed as homogeneous or heterogeneous through visual evaluation of the presence of necrosis, cyst, hemorrhage, and calcification, and pattern of enhancement. RESULTS: We found a strong linear correlation between the Cho value and the Ki-67 labeling index in the 18 homogeneous gliomas, but no correlation was found in the eight heterogeneous gliomas, which turned out to be malignant. CONCLUSION: The semiquantitative Cho value is a reliable predictor of proliferative activity of gliomas when the tumor appears homogeneous on MR images.

Noninvasive evaluation of malignancy of brain tumors with proton MR spectroscopy.

PURPOSE: To test clinical proton MR spectroscopy as a noninvasive method for predicting tumor malignancy. METHODS: Water-suppressed single-voxel point resolved spectroscopy in the frontal white matter of 17 healthy volunteers and 25 patients with brain tumors yielded spectra with peaks of N-acetyl aspartate (NAA), choline-containing compounds (Cho), creatine/phosphocreatine (Cre), and lactate. These peak intensities were semiquantitated as a ratio to that of the external reference. The validity of the semiquantitation was first evaluated through phantom and volunteer experiments. RESULTS: The variation in measurements of the designated region in the volunteers was less than 10%. Normal ranges of NAA/reference, Cho/reference, and Cre/reference were 3.59 +/- 0.68, 1.96 +/- 0.66, and 1.53 +/- 0.64 (mean +/- SD), respectively. In 17 gliomas, the Cho/reference value in high-grade gliomas was significantly higher than in low-grade gliomas. Levels of NAA/reference were also significantly different in low-grade and high-grade malignancy. In eight meningiomas (four newly diagnosed and four recurrent), the level of Cho/reference was significantly higher in recurrent meningiomas than in normal white matter or in newly diagnosed meningiomas. CONCLUSIONS: Higher grades of brain tumors in this study were associated with higher Cho/reference and lower NAA/reference values. These results suggest that clinical proton MR spectroscopy may help predict tumor malignancy.

Thallium-201 single-photon emission computed tomographic and proton magnetic resonance spectroscopic characteristics of intracranial ganglioglioma: three technical case reports.

OBJECTIVE: The correlation between thallium-201 (201TI) uptake, semiquantitative choline-containing compound values measured by proton magnetic resonance spectroscopy (1H-MRS), and Ki-67 labeling indexes (LIs) was investigated in three gangliogliomas. METHODS: The early and delayed 201TI indexes were calculated as the ratio of tumor to normal brain tissue uptake by 201TI single-photon emission computed tomography. Single-voxel 1H-MRS was performed to measure the levels of metabolites in the tumors. Ki-67 LI was measured in the surgical specimens. RESULTS: All three gangliogliomas showed very high 201TI uptake on both early and delayed images. 1H-MRS demonstrated malignancy based on the high choline peak relative to the creatine and N-acetylaspartate peaks. Ki-67 LI was less than 1% in two gangliogliomas and 3.5% in an anaplastic ganglioglioma. CONCLUSION: Both 201TI single-photon emission computed tomography and 1H-MRS indicated malignancy, whereas Ki-67 LI indicated low growth activity. 201TI single-photon emission computed tomography and 1H-MRS of ganglioglioma might be affected by metabolic characteristics other than growth activity.

Recurrent germinoma in the optic nerve: report of two cases.

OBJECTIVE AND IMPORTANCE: Intracranial germinomas often disseminate via the ventricular and subarachnoid pathways, but seeding to the perioptic arachnoid space is extremely unusual. We report two cases of recurrent germinoma seeding in the optic nerve. CLINICAL PRESENTATION: Two men with pure germinoma were initially treated with three cycles of a three-drug regimen of bleomycin, etoposide, and cisplatin, and a complete response was achieved. Patient 1 experienced ventricle wall dissemination 10 months after undergoing the initial treatment and was successfully treated with three cycles of carboplatin and etoposide and then by 24-Gy whole-ventricle radiation. Twelve months later, he complained of progressive visual acuity loss, and magnetic resonance imaging demonstrated bilateral enhancement of the optic nerves. Patient 2 also experienced ventricle wall dissemination 3 months after undergoing the initial chemotherapy, but he exhibited a complete response after undergoing 24-Gy whole-ventricle radiation. Two years later, he complained of progressive visual acuity loss. Magnetic resonance imaging demonstrated bilateral enhancement of the optic nerves and cerebellar hemispheres. INTERVENTION: None of the locations of recurrence were included in the irradiation field, whereas there was no recurrence within the radiation field. Complete responses were obtained with three cycles of a three-drug regimen of ifosfamide, cisplatin, and etoposide and then by 24-Gy whole-brain radiation that included the bilateral optic nerves. The visual acuity of each patient improved slightly. CONCLUSION: Delayed seeding in the optic nerve may result from germinoma cells that remain dormant, so they cannot be destroyed by chemotherapy regimens alone.

Two cases of giant serpentine aneurysm.

Giant serpentine aneurysm (GSA) is an entity defined on radiological and pathological grounds as a giant, partially thrombosed aneurysm containing tortuous vascular channels. We have had the opportunity to study two patients with GSAs, which has allowed for a complete comparative anatomical and radiological study. This report emphasizes the etiology of the GSAs. Twenty-two patients with GSAs have been reported in the literature, of which pathological studies were done in 10. In most of these, the aneurysm was found to be filled with an organized thrombus, but in our patients the aneurysm was filled with relatively new clot. The aneurysm enlarged and a change in the tortuous vascular channel was observed over a period of 1 year in the first patient, whereas a globoid aneurysm developed into a GSA in the brief period of just 2 weeks in the second patient. This rapid transformation of a globoid aneurysm into a GSA is of particular interest when the etiology of GSAs is considered. Our patients therefore shed some interesting light on the possible pathophysiology of GSAs. That is, the bloodstream may change dynamically in a giant aneurysm and may become a serpentine channel under conditions that lead to a "Coanda effect."

Antineoplaston AS2-1 for maintenance therapy in liver cancer.

Antineoplaston AS2-1 exhibits cytostatic growth inhibition of human hepatocellular carcinoma cells in vitro and showed minimum adverse effects in a phase I clinical trial. Liver cancer is difficult to control because of multicentricity and underlying liver disease. We reviewed two clinical cases of liver cancer (hepatocellular carcinoma and multiple liver metastases from colon cancer) in whom we believe antineoplaston A2-1 was useful as a maintenance therapy after transcatheter arterial embolization (TAE) and microwave coagulation necrosis (MCN). The two patients have continued to be in good condition for more than two years without limitation of their normal activities. Antineoplaston AS2-1 may be effective and useful as a maintenance agent after TAE and MCN in patients with liver cancer.

Quick response of advanced cancer to chemoradiation therapy with antineoplastons.

Antineoplastons A10 and AS2-1 exhibit growth inhibition of cancer cells by diverse modes of action. We observed antitumor responses within 2-3 weeks of a combination treatment of chemoradiation therapy and antineoplastons A10 and AS2-1 in phase I clinical study being conducted in Kurume University Hospital. We reviewed 3 clinical cases of advanced cancer (multiple metastatic lung cancer, thalamic glioma and primary lung cancer) in which we believed antineoplaston A10 and AS2-1 may be contributing to the rapid antitumor response. The possible use of this combination for induction therapy in advanced cancer is discussed.