[Surgical Case of Accidental Infantile Acute Subdural Hematoma Caused by Household Minor Head Trauma:Hyperperfusion during Postoperative Hemispheric Hypodensity, Namely "Big Black Brain"].

We experienced a case of an accidental infantile acute subdural hematoma caused by household minor head trauma(Nakamura type I intracranial hemorrhage)with postoperative hemispheric hypodensity lesion(Big Black Brain)whose pathophysiology was analyzed using perfusion MRI. A ten-month-old boy was admitted to our hospital in a comatose state. His mother revealed that the boy suffered a fall from a sofa bed. A CT scan indicated massive acute subdural hematoma in the left cerebral hemisphere. Emergency craniotomy and hematoma evacuation were performed. On postoperative day 3, CT revealed hemispheric hypodensity, and the boy suffered from status epilepticus. MRI on the following day showed widespread white matter hyperintensity in diffusion-weighted images, and MRA demonstrated dilation of the middle cerebral artery. Perfusion MRI using the dynamic susceptibility contrast method revealed a marked increase in cerebral blood flow in the left hemisphere. These abnormal MRI and MRA findings disappeared on postoperative day 13. Status epilepticus also improved upon administration of multi-antiepileptic drugs. Fundoscopy findings on postoperative day 3 showed small bilateral petechial or brush retinal hemorrhages. However, whole-body examination did not show any problems, and was consistent with the mother's account. Thus, we judged non-abusive head trauma. Although follow-up MRI showed diffuse atrophy of the left cerebral hemisphere, the boy aged well without obvious paresis or verbal developmental delay as judged by a follow-up more than a year later. Based on these results, we speculated that hyperperfusion caused by dilation of the cerebral artery was related to the postoperative hemispheric hypodensity, namely "Big Black Brain".

[Bilateral Internal Carotid Artery Dissection Caused by Elongated Styloid Processes:A Case Report].

We report a case of bilateral internal carotid artery(ICA)dissection associated with bilateral elongated styloid processes(ESPs). A 46-year-old man presented with transient aphasia and left visual disturbance at a business meeting. He complained of a foreign body sensation in his throat during swallowing for two years. Magnetic resonance imaging(MRI)demonstrated fresh small infarcts in the left corona radiata. Magnetic resonance angiography(MRA)revealed string signs bilaterally in the cervical ICAs. The patient was diagnosed with bilateral idiopathic ICA dissection and was treated with ozagrel and clopidogrel. Three-dimensional computed tomographic angiogram(3DCTA)indicated bilateral ESPs and bilateral ICA stenosis. 3DCTA with the patient's head tilting and neck extension revealed that each ICA was compressed by the ipsilateral ESP. A follow-up MRA showed complete normalization of bilateral ICAs after neck rest and anti-platelet therapy, following which, clopidogrel was stopped. The patient wore a soft cervical collar until the operation, to avoid contact between the ESPs and ICAs due to changes in head position. Bilateral ESP resection was performed to prevent recurrence of cerebral ischemic events caused by ICA dissection. The patient was discharged one week after the surgery without any neurological deficit. There was no recurrence of symptoms during the next eight months after the operation.

miR-493 induction during carcinogenesis blocks metastatic settlement of colon cancer cells in liver.

Liver metastasis is a major lethal complication associated with colon cancer, and post-intravasation steps of the metastasis are important for its clinical intervention. In order to identify inhibitory microRNAs (miRNAs) for these steps, we performed 'dropout' screens of a miRNA library in a mouse model of liver metastasis. Functional analyses showed that miR-493 and to a lesser extent miR-493(*) were capable of inhibiting liver metastasis. miR-493 inhibited retention of metastasized cells in liver parenchyma and induced their cell death. IGF1R was identified as a direct target of miR-493, and its inhibition partially phenocopied the anti-metastatic effects. High levels of miR-493 and miR-493(*), but not pri-miR-493, in primary colon cancer were inversely related to the presence of liver metastasis, and attributed to an increase of miR-493 expression during carcinogenesis. We propose that, in a subset of colon cancer, upregulation of miR-493 during carcinogenesis prevents liver metastasis via the induction of cell death of metastasized cells.

Gene expression signature-based prognostic risk score in patients with glioblastoma.

The present study aimed to identify genes associated with patient survival to improve our understanding of the underlying biology of gliomas. We investigated whether the expression of genes selected using random survival forests models could be used to define glioma subgroups more objectively than standard pathology. The RNA from 32 non-treated grade 4 gliomas were analyzed using the GeneChip Human Genome U133 Plus 2.0 Expression array (which contains approximately 47 000 genes). Twenty-five genes whose expressions were strongly and consistently related to patient survival were identified. The prognosis prediction score of these genes was most significant among several variables and survival analyses. The prognosis prediction score of three genes and age classifiers also revealed a strong prognostic value among grade 4 gliomas. These results were validated in an independent samples set (n = 488). Our method was effective for objectively classifying grade 4 gliomas and was a more accurate prognosis predictor than histological grading.

Dopamine D1 receptors control exercise hyperpnoea in mice.

Previously, we undertook simultaneous recording of ventilation and pulmonary gas exchange in mice and revealed that dopamine D(2) receptors participate in exercise hyperpnoea via behavioural control of ventilation with unchanged pulmonary gas exchange. Here, we examined the hypothesis that D(1) receptors also contribute to exercise hyperpnoea using a D(1) receptor antagonist (SCH 23390; SCH) that crosses the blood-brain barrier, with the same recording technique and protocol as in the previous study. The respiratory responses of mice injected with saline or SCH (50 µg (kg body weight)(-1), i.p.) were compared during constant-load exercise at 6 m min(-1). Each mouse was set in an airtight treadmill chamber equipped with a differential pressure transducer and open-circuit system with a mass spectrometer. At rest, SCH-injected mice had significantly reduced respiratory frequency, minute ventilation and pulmonary gas exchange compared with saline-injected mice. Ventilation during hyperoxic gas inhalation and hypercapnic ventilatory responses between groups were similar. Abrupt increases and sequential declines to the steady-state level were produced by treadmill exercise in both groups of mice. Treatment with SCH lowered the increased levels of respiratory frequency, tidal volume and minute ventilation during the steady state, as well as reducing the O(2) uptake, CO(2) output and body temperature throughout treadmill exercise. These data suggest that D(1) receptors contribute to a resting ventilation level and exercise hyperpnoea during the steady state in parallel with metabolic changes. Notably, the metabolic control of D(1) receptors was important for maintenance of the steady state, and D(1) receptors in hypothalamic nuclei could be involved in this modulation.

Prediction of tissue-of-origin of early stage cancers using serum miRNomes.

BACKGROUND: Noninvasive detection of early stage cancers with accurate prediction of tumor tissue-of-origin could improve patient prognosis. Because miRNA profiles differ between organs, circulating miRNomics represent a promising method for early detection of cancers, but this has not been shown conclusively. METHODS: A serum miRNA profile (miRNomes)-based classifier was evaluated for its ability to discriminate cancer types using advanced machine learning. The training set comprised 7931 serum samples from patients with 13 types of solid cancers and 5013 noncancer samples. The validation set consisted of 1990 cancer and 1256 noncancer samples. The contribution of each miRNA to the cancer-type classification was evaluated, and those with a high contribution were identified. RESULTS: Cancer type was predicted with an accuracy of 0.88 (95% confidence interval [CI] = 0.87 to 0.90) in all stages and an accuracy of 0.90 (95% CI = 0.88 to 0.91) in resectable stages (stages 0-II). The F1 score for the discrimination of the 13 cancer types was 0.93. Optimal classification performance was achieved with at least 100 miRNAs that contributed the strongest to accurate prediction of cancer type. Assessment of tissue expression patterns of these miRNAs suggested that miRNAs secreted from the tumor environment could be used to establish cancer type-specific serum miRNomes. CONCLUSIONS: This study demonstrates that large-scale serum miRNomics in combination with machine learning could lead to the development of a blood-based cancer classification system. Further investigations of the regulating mechanisms of the miRNAs that contributed strongly to accurate prediction of cancer type could pave the way for the clinical use of circulating miRNA diagnostics.

Dopaminergic modulation of exercise hyperpnoea via D(2) receptors in mice.

Dopamine is related to behaviour (including arousal, motivation and motor control of locomotion), and its turnover in the brain is increased during exercise. We examined the hypothesis that dopamine D(2) receptors contribute to exercise hyperpnoea via central neural pathways using the D(2)-like receptor antagonist, raclopride. We simultaneously measured ventilation and pulmonary gas exchange for the first time in mice. Mice injected with saline and raclopride (2 mg (kg body weight)(-1); i.p.) were compared for respiratory responses to constant-load exercise at 6 m min(-1). Each mouse was set in an airtight treadmill chamber. In the resting state, raclopride-treated mice had reduced respiratory frequency (f(R)) and minute ventilation (V) compared with saline-treated mice, but arterial P(CO(2)) and pulmonary gas exchange were not affected, showing that alveolar ventilation was maintained. Inhalation of hyperoxic gas maintained V in saline-treated mice, and hypercapnic ventilatory responses between the two groups were similar. Treadmill exercise produced an abrupt increase in V to a maximal level within 1 min and declined to a steady-state level in both groups. Raclopride-treated mice had reduced f(R) and V compared with saline-treated mice during steady states, but showed a similar increase in f(R) and V at exercise onset. Minute ventilation in the steady state was controlled, along with the increase in pulmonary O(2) uptake in both groups, but was lowered in raclopride-treated mice. Thus, D(2) receptors participate in resting breathing patterns to raise f(R) and exercise hyperpnoea in the steady state, probably through behavioural control and not central motor command, at exercise onset.

Mechanical Thrombectomy for Bihemispheric Infarction Caused by Acute Unilateral Internal Carotid Artery Occlusion in a Patient with Contralateral Chronic Carotid Occlusion: A Case Report.

Objective: We report a patient with acute bihemispheric infarction who underwent mechanical thrombectomy. Case Presentation: A 76-year-old man suddenly developed coma and quadriplegia. Brain MRI and MRA revealed acute bihemispheric infarction due to occlusions of both the internal carotid arteries (ICAs). According to the DSA findings, we considered the left ICA as chronic occlusion and the right as acute. Mechanical thrombectomy for the right ICA occlusion was performed. Total recanalization was achieved using a stent retriever 181 minutes after onset. The left hemisphere was perfused by cross circulation through the anterior communicating artery, but the symptoms did not improve. MRI the day after thrombectomy showed extensive bihemispheric infarction. Recanalization for the bilateral hemispheres was maintained, although the left ICA remained occluded. He died 2 months later due to gastrointestinal bleeding. Conclusion: Acute bihemispheric infarction due to occlusions of both ICAs is a rare entity. The symptoms are very severe and the therapeutic time window is extremely short because of absent collateral pathways. We should consider pre-existing carotid occlusive disease, determine whether the occlusions are acute or chronic, and perform prompt therapy. Further investigation is warranted to obtain a better outcome.

Fluoride-bridged dinuclear dysprosium complex showing single-molecule magnetic behavior: supramolecular approach to isolate magnetic molecules.

Using Na-encapsulated benzo[18]crown-6 (Na)(B18C6) as a counter cation, we successfully magnetically isolated a fluoride-bridging Dy dinuclear complex {[(PW11O39)Dy(H2O)2]2F} (Dy2POM) with lacunary Keggin ligands. (Na)(B18C6) formed two types of tetramers through C-H⋯O, π⋯π and C-H⋯π interactions, and each tetramer aligned in one dimension along the c-axis to form two types of channels. One channel was partially penetrated by a supramolecular cation from the ±a-axis direction, dividing the channel in the form of a "bamboo node". Dy2POM was spatially divided by this "bamboo node," which magnetically isolated one portion from the other. The temperature dependence of the magnetic susceptibility indicated a weak ferromagnetic interaction between the Dy ions bridged by fluoride. Dy2POM exhibited the magnetic relaxation characteristics of a single-molecule magnet, including the dependence of AC magnetic susceptibility on temperature and frequency. Magnetic relaxation can be described by the combination of thermally active Orbach and temperature-independent quantum tunneling processes. The application of a static magnetic field effectively suppressed the relaxation due to quantum tunneling.

Ultrasound image-guided gene delivery using three-dimensional diagnostic ultrasound and lipid-based microbubbles.

Gene therapy is a promising technology for genetic and intractable diseases. Drug delivery carriers or systems for genes and nucleic acids have been studied to improve transfection efficiency and achieve sufficient therapeutic effects. Ultrasound (US) and microbubbles have also been combined for use in gene delivery. To establish a clinically effective gene delivery system, exposing the target tissues to US is important. The three-dimensional (3D) diagnostic probe can three-dimensionally scan the tissue with mechanical regulation, and homogenous US exposure to the targeted tissue can be expected. However, the feasibility of therapeutically applying 3D probes has not been evaluated, especially gene delivery. In this study, we evaluated the characteristics of a 3D probe and lipid-based microbubbles (LB) for gene delivery and determined whether the 3D probe in the diagnostic US device could be used for efficient gene delivery to the targeted tissue using a mouse model. The 3D probe RSP6-16 with LB delivered plasmid DNA (pDNA) to the kidney after systemic injection with luciferase activity similar to that of probes used in previously studies. No toxicity was observed after treatment and, therefore, the combined 3D probe and LB would deliver genes to targeted tissue safely and efficiently.

NADPH oxidase overexpression in human colon cancers and rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

NADPH oxidase/dual-oxidase (Nox/Duox) family members have been implicated in nuclear factor kappa-B (NFκB)-mediated inflammation and inflammation-associated pathologies. We sought to examine, for the first time, the role of Nox/Duox and NFκB in rats treated with the cooked meat heterocyclic amine carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). In the PhIP-induced colon tumors obtained after 1 year, Nox1, Nox4, NFκB-p50 and NFκB-p65 were all highly overexpressed compared with their levels in adjacent normal-looking colonic mucosa. Nox1 and Nox4 mRNA and protein levels also were markedly elevated in a panel of primary human colon cancers, compared with their matched controls. In HT29 human colon cancer cells, Nox1 knockdown induced G1 cell cycle arrest, whereas in Caco-2 cells there was a strong apoptotic response, with increased levels of cleaved caspase-3, -6, -7 and poly(ADP-ribose)polymerase. Nox1 knockdown blocked lipopolysaccharide-induced phosphorylation of IκB kinase, inhibited the nuclear translocation of NFκB (p50 and p65) proteins, and attenuated NFκB DNA binding activity. There was a corresponding reduction in the expression of downstream NFκB targets, such as MYC, CCND1 and IL1ß. The results provide the first evidence for a role of Nox1, Nox4 and NFκB in PhIP-induced colon carcinogenesis, including during the early stages before tumor onset. Collectively, the findings from this investigation and others suggest that further work is warranted on the role of Nox/Duox family members and NFκB in colon cancer development.

Systematic exploration of cancer-associated microRNA through functional screening assays.

MicroRNA (miRNA), non-coding RNA of approximately 22 nucleotides, post-transcriptionally represses expression of its target genes. miRNA regulates a variety of biological processes such as cell proliferation, cell death, development, stemness and genomic stability, not only in physiological conditions but also in various pathological conditions such as cancers. More than 1000 mature miRNA have been experimentally identified in humans and mice, yet the functions of a vast majority of miRNA remain to be elucidated. Identification of novel cancer-associated miRNA seems promising considering their possible application in the development of novel cancer therapies and biomarkers. Currently, there are two major approaches to identify miRNA that are associated with cancer: expression profiling study and functional screening assay. The former approach is widely used, and a large number of studies have shown aberrant miRNA expression profiles in cancer tissues compared with their non-cancer counterparts. Although aberrantly expressed miRNA are potentially good biomarkers, in most cases a majority of them do not play causal roles in cancers when functional assays are performed. In contrast, the latter approach allows screening of 'driver' miRNA with cancer-associated phenotypes, such as cell proliferation and cell invasion. Thus, this approach might be suitable in finding crucial targets of novel cancer therapy. The combination of both types of approaches will contribute to further elucidation of the cancer pathophysiology and to the development of a novel class of cancer therapies and biomarkers.

Functional screening using a microRNA virus library and microarrays: a new high-throughput assay to identify tumor-suppressive microRNAs.

MicroRNA (miRNA) is a class of non-coding RNAs that represses expression of target messenger RNAs posttranscriptionally. A growing body of evidence supports their roles in various normal cellular processes, as well as in pathological conditions, such as cancer. We established a functional screening assay that enables high-throughput identification of miRNAs that have a role in cancer phenotypes of interest, via the combination of pooled lentivirus vectors expressing several hundred miRNA precursors and a custom-made microarray. Self versus self-hybridization analysis using pooled polymerase chain reaction products generated highly linear and reproducible results. To test the feasibility of the assay, we focused on miRNAs that control proliferation of pancreatic cancer cells and successfully identified five miRNAs that negatively control cell proliferation, including miRNA-34a that was previously identified as a representative tumor-suppressive miRNA. The results were further validated using lentivirus vectors expressing each of the five miRNAs or synthetic miRNAs. The function-based nature of the assay enabled identification of miRNAs that were strongly linked to cell proliferation, but the relative ease and flexibility of the assay allow for future studies of cancer stem cells, metastasis and other cancer phenotypes of interest.

MicroRNA, SND1, and alterations in translational regulation in colon carcinogenesis.

Post-transcriptional regulation of gene expression by microRNA (miRNA) has recently attracted major interest in relation to its involvement in cancer development. miRNA is a member of small non-coding RNA, consists of 22-24 nucleotides and regulates expression of target mRNA species in a post-transcriptional manner by being incorporated with RNA-induced silencing complex (RISC). Staphylococcal nuclease homology domain containing 1 (SND1), a component of RISC, is frequently up-regulated in human colon cancers and also chemically induced colon cancers in animals. We here showed that SDN1 is involved in miRNA-mediated gene suppression and overexpression of SND1 in colon cancer cells causes down-regulation of APC without altering APC mRNA levels. As for the miRNA expression profile in human colon cancer, miR-34a was among the list of down-regulated miRNA. Expression of miR-34a is tightly regulated by p53, and ectopic expression of miR-34a in colon cancer cells causes remarkable reduction of cell proliferation and induces senescence-like phenotypes. MiR-34a also participates in the positive feedback loop of the p53 tumor suppressor network. This circuitry mechanism for p53 activation is of interest in understanding the tumor suppressive function of miR-34a in colon carcinogenesis. miRNA should also be considered as novel anti-cancer agents in tumor suppressive therapeutic applications.

Overlapping Stents and Coil Embolization of Ruptured Anterior Cerebral Artery Dissecting Aneurysms in the Acute Phase.

Objective: To report a case of ruptured anterior cerebral artery dissection treated with stent-assisted coil embolization with overlapping stents. Case Presentation: A 51-year-old woman developed subarachnoid hemorrhage the day after transient left hemiparesis. Angiography revealed a ruptured anterior cerebral artery dissecting aneurysm. We conducted stent-assisted coil embolization with the overlapping stent technique on the day after the hemorrhage. She recovered steadily without rebleeding. Six months after embolization, no recurrence was found on angiography. Conclusion: Although an acceptable result was achieved in this case, the safety and efficacy of this procedure are unconfirmed. A larger number of cases should be accumulated.

SND1, a component of RNA-induced silencing complex, is up-regulated in human colon cancers and implicated in early stage colon carcinogenesis.

Colon cancers have been shown to develop after accumulation of multiple genetic and epigenetic alterations with changes in global gene expression profiles, contributing to the establishment of widely diverse phenotypes. Transcriptional and posttranscriptional regulation of gene expression by small RNA species, such as the small interfering RNA and microRNA and the RNA-induced silencing complex (RISC), is currently drawing major interest with regard to cancer development. SND1, also called Tudor-SN and p100 and recently reported to be a component of RISC, is among the list of highly expressed genes in human colon cancers. In the present study, we showed remarkable up-regulation of SND1 mRNA in human colon cancer tissues, even in early-stage lesions, and also in colon cancer cell lines. When mouse Snd1 was stably overexpressed in IEC6 rat intestinal epithelial cells, contact inhibition was lost and cell growth was promoted, even after the cells became confluent. Intriguingly, IEC6 cells with high levels of Snd1 also showed an altered distribution of E-cadherin from the cell membrane to the cytoplasm, suggesting loss of cellular polarity. Furthermore, the adenomatous polyposis coli (Apc) protein was coincidentally down-regulated, with no significant changes in the Apc mRNA level. Immunohistochemical analysis using chemically induced colonic lesions developed in rats revealed overexpression of Snd1 not only in colon cancers but also in aberrant crypt foci, putative precancerous lesions of the colon. Up-regulation of SND1 may thus occur at a very early stage in colon carcinogenesis and contribute to the posttranscriptional regulation of key players in colon cancer development, including APC and beta-catenin.

A serum microRNA classifier for the diagnosis of sarcomas of various histological subtypes.

Due to their rarity and diversity, sarcomas are difficult to diagnose. Consequently, there is an urgent demand for a novel diagnostic test for these cancers. In this study, we investigated serum miRNA profiles from 1002 patients with bone and soft tissue tumors representing more than 43 histological subtypes, including sarcomas, intermediate tumors, and benign tumors, to determine whether serum miRNA profiles could be used to specifically detect sarcomas. Circulating serum miRNA profiles in sarcoma patients were clearly distinct from those in patients with other types of tumors. Using the serum levels of seven miRNAs, we developed a molecular detector, Index VI, that could distinguish sarcoma patients from benign and healthy controls with remarkably high sensitivity (90%) and specificity (95%), regardless of histological subtype. Index VI provides an approach to the early and precise detection of sarcomas, potentially leading to curative treatment and longer survival.

Results of treatment of 112 cases of primary CNS lymphoma.

BACKGROUND: Chemotherapy with or without radiotherapy is the mainstay of treatment for primary central nervous system lymphoma (PCNSL). High-dose methotrexate (MTX) is the most effective drug available to treat these lesions, either as a single agent or in combination with other drugs. Due to the lack of well-conducted randomized trials, the optimal treatment remains controversial. Available retrospective studies are difficult to discuss, however, some common themes can be found. METHODS: One hundred and twelve patients with PCNSL were treated with four different regimens over a period of 24 years. Treatment regimens were: whole-brain irradiation (WBI) alone, MVP (MTX, vincristine, and predonisolone), ProMACE-MOPP hybrid (cyclophosphamide, pirarubicin, etoposide, vincristine, procarbazine, prednisone, and MTX) and R-MTX (rituximab, MTX, pirarubicin, procarbazine, and prednisone) combined-modality therapy. RESULTS: The median failure-free survival was 16 months, and the median overall survival (OS) was 24 months. The 2- and 5-year actuarial probability of survival was 52.4 +/- 4.8% [95% confidence intervals (CI)] and 30.2 +/- 4.8% (95% CI), respectively. The ProMACE-MOPP protocol, Karnofsky performance status (KPS), MTX dose and WBI were associated with good OS by univariate models. By multivariate analysis, MTX dose, WBI dose, and its square dose were significantly associated with good OS. 20-30 Gy WB, and 500 mg/m(2) of MTX dose appeared important determinants of OS. CONCLUSIONS: A modest dose of MTX (500 mg/m(2)) followed by reduced-dose WBI for patients who respond appears a feasible treatment approach that minimizes serious toxicity.

A Nucleolar Stress-Specific p53-miR-101 Molecular Circuit Functions as an Intrinsic Tumor-Suppressor Network.

BACKGROUND: Activation of intrinsic p53 tumor-suppressor (TS) pathways is an important principle underlying cancer chemotherapy. It is necessary to elucidate the precise regulatory mechanisms of these networks to create new treatment strategies. METHODS: Comprehensive analyses were carried out by microarray. Expression of miR-101 was analyzed by clinical samples of lung adenocarcinomas. FINDINGS: We discovered a functional link between p53 and miR-101, which form a molecular circuit in response to nucleolar stress. Inhibition of RNA polymerase I (Pol I) transcription resulted in the post-transcriptional activation of miR-101 in a p53-dependent manner. miR-101 induced G2 phase-specific feedback regulation of p53 through direct repression of its target, EG5, resulting in elevated phosphorylation of ATM. In lung cancer patients, low expression of miR-101 was associated with significantly poorer prognosis exclusively in p53 WT cases. miR-101 sensitized cancer cells to Pol I transcription inhibitors and strongly repressed xenograft growth in mice. Interestingly, the most downstream targets of this circuit included the inhibitor of apoptosis proteins (IAPs). Repression of cIAP1 by a selective inhibitor, birinapant, promoted activation of the apoptosis induced by Pol I transcription inhibitor in p53 WT cancer cells. INTERPRETATION: Our findings indicate that the p53-miR-101 circuit is a component of an intrinsic TS network formed by nucleolar stress, and that mimicking activation of this circuit represents a promising strategy for cancer therapy. FUND: National Institute of Biomedical Innovation, Ministry of Education, Culture, Sports & Technology of Japan, Japan Agency for Medical Research and Development.

Salvage therapy and late neurotoxicity in patients with recurrent primary CNS lymphoma treated with a modified ProMACE-MOPP hybrid regimen.

We report the efficacy of salvage therapy with a modified ProMACE-MOPP combined with radiation in patients with primary central nervous system lymphoma (PCNSL). Thirty-two immunocompetent patients were treated with a regimen of pirarubicin, cyclophosphamide, etoposide, vincristin, and methotrexate (MTX: 500 mg/m(2)) administered in 21-day cycles. Patients received 20 Gy of whole-brain radiotherapy after three cycles of chemotherapy. A single cycle of chemotherapy was repeated every four months for two years. Nine patients with CNS relapse were retreated with additional cycles of the ProMACE-MOPP hybrid regimen with a 90% objective response rate. Median complete response (CR) duration was 13.2 months and median survival time (MST) for the nine patients treated after initial relapse was 30 months. One of 17 patients (5.8%) who had less than 20 Gy of whole brain irradiation developed dementia. In contrast, six of seven (85.7%) patients who had more than 30 Gy of whole brain radiotherapy became demented. Maintaining a moderate dose of MTX, while adding chemotherapeutic agents and 20 Gy of whole brain radiation therapy, improved disease control and overall survival and lowered the incidence of delayed neurologic toxicity in patients with PCNSL. Additional treatment with a ProMACE-MOPP hybrid regimen is still effective for relapsed disease.