The impact of rare cancer and early-line treatments on the benefit of comprehensive genome profiling-based precision oncology.

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

Topological charge transport by mobile dielectric-ferroelectric domain walls.

The concept of topology has been widely applied in condensed matter physics, leading to the identification of peculiar electronic states on three-dimensional (3D) surfaces or 2D lines separating topologically distinctive regions. In the systems explored so far, the topological boundaries are built-in walls; thus, their motional degrees of freedom, which potentially bring about new paradigms, have been experimentally inaccessible. Here, working with a quasi-1D organic material with a charge-transfer instability, we show that mobile neutral-ionic (dielectric-ferroelectric) domain boundaries with topological charges carry strongly 1D-confined and anomalously large electrical conduction with an energy gap much smaller than the one-particle excitation gap. This consequence is further supported by nuclear magnetic resonance detection of spin solitons, which are required for steady current of topological charges. The present observation of topological charge transport may open a new channel for broad charge transport-related phenomena such as thermoelectric effects.

Evidence for solitonic spin excitations from a charge-lattice-coupled ferroelectric order.

Topological defects have been explored in different fields ranging from condensed matter physics and particle physics to cosmology. In condensed matter, strong coupling between charge, spin, and lattice degrees of freedom brings about emergent excitations with topological characteristics at low energies. One-dimensional (1D) systems with degenerate dimerization patterns are typical stages for the generation of topological defects, dubbed "solitons"; for instance, charged solitons are responsible for high electrical conductivity in doped trans-polyacetylene. Here, we provide evidence based on a nuclear magnetic resonance (NMR) study for mobile spin solitons deconfined from a strongly charge-lattice-coupled spin-singlet ferroelectric order in a quasi-1D organic charge-transfer complex. The NMR spectral shift and relaxation rate associated with static and dynamic spin susceptibilities indicate that the ferroelectric order is violated by dilute solitonic spin excitations, which were further demonstrated to move diffusively by the frequency dependence of the relaxation rate. The traveling solitons revealed here may promise the emergence of anomalous electrical and thermal transport.

Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study.

BACKGROUND: The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. RESULTS: As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. CONCLUSIONS: Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. CLINICAL TRIALS NUMBER: Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071.

CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab.

BACKGROUND: CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era. PATIENTS AND METHODS: We analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab. RESULTS: No significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P < 0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease. CONCLUSIONS: Our results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.

Ganglioglioma originating in the cerebellum with a large cyst--a case report and review of the literature.

Here we report a rare case of cerebellar ganglioglioma accompanied by a large cyst, and present a review of the reported 28 cases with cerebellar ganglioglioma. An otherwise healthy 46-year-old woman complained of gradual headache and truncal ataxia. MRI revealed a huge cystic lesion with a mural nodule in the left cerebellar hemisphere. The tumor was resected totally. Histologically, it was composed of neuronal and glial elements, and was accordingly diagnosed as ganglioglioma.

MRI of ectopic posterior pituitary bright spot with large adenomas: appearances and relationship to transient postoperative diabetes insipidus.

MRI of large pituitary adenomas has revealed that a posterior pituitary bright spot (PPBS), comprising ADH-containing neurosecretory granules, is commonly ectopic before surgery and attached to the tip of the pituitary stalk late after surgery. Although the PPBS indicates functional integrity of the posterior lobe, transient diabetes insipidus (DI), caused by deficiency of ADH, is frequent early after surgery. We attempted to clarify how the shape, signal intensity and site of the PPBS before surgery are related to transient DI in the early postoperative period. We carried out MRI on 15 patients with a large adenoma and an ectopic PPBS before surgery and then within 1 week (early), 1-2 months (intermediate) and 6 or more months (late) after the operation. There were nine who had transient DI, which subsided by the intermediate study; none had permanent DI. Regardless of transient DI, the PPBS was visible, and its signal intensity was similar, on all postoperative studies. Although 11 did not change in shape, four showed a remarkable change from a flat shape before surgery to a rounded one postoperatively. On the intermediate MRI, the PPBS had descended to the level of the diaphragma as mass effect disappeared.

Demonstration of the optic pathway in large pituitary adenoma on heavily T2 weighted MR images.

The objective of the investigation was to understand preoperatively the detailed anatomical relationship of large pituitary adenomas to surrounding structures, using the heavily T2-weighted reversed (T2R) MR images. This study consisted of 28 patients with pituitary adenoma, presenting with visual disturbance. The MRI scanner used was a Gyroscan ACSNT 1.5T and the slice thickness of the image was 3 mm with 0.5 mm interslice gap. The relation of pituitary adenoma to optic pathway and to the degree of visual field defect was assessed. Relations of the optic chiasm to adenoma were classified into three types: anterior, superior and posterior. The optic chiasm was directly visualized and identifiable in all patients studied. It was located anterior in four cases, superior in 22 and posterior in two in relation to the adenoma. Its location was further confirmed by the anatomical delineation of surrounding structures such as anterior commissure and lamina terminalis. Optic nerve or tract was unidentifiable in one case, for each category. Detectability of each optic component was higher on T2R images than on conventional T1-weighted images. The adenoma extended into and in front of the third ventricle in anterior and posterior types, respectively. The anterior communicating artery complex and the optic pathway were relocated together in anterior and superior types, and were separated in the posterior type. In a case of the posterior type, the complex was sectioned to obtain a wider surgical field during anterior interhemispheric approach. While degrees of visual field defect were proportional to tumour size in the superior type, they were unrelated in the anterior and posterior types. On choosing a transcranial approach, the transcallosal route is unsuitable for an adenoma of posterior type, which extends in front of the third ventricle. This preoperative MRI information makes it possible to visualize directly the optic pathway even in huge adenomas, and is useful in predicting surgical anatomy and selecting a proper surgical approach.

Heavily T2 weighted MR images of anterior optic pathways in patients with sellar and parasellar tumours - prediction of surgical anatomy.

OBJECTIVE: Location of anterior optic pathways in sellar and parasellar tumours was preoperatively evaluated, by use of heavily T2 weighted MR images. METHODS: Heavily T2 and conventional T1 weighted images were studied in 20 patients with sellar and parasellar tumours who underwent craniotomy. Pathology revealed pituitary adenoma in 5 patients, craniopharyngioma in 8 and parasellar meningioma in 7. Maximum sizes ranged from 15 mm to 58 mm. Sequence parameters of TR/TE for heavily T2 weighted and T1 weighted images were 5800/220 msec and 600/20 msec, respectively, and slice thickness was 3 mm for both. RESULTS: The anterior optic pathway was detected in 95% on heavily T2 weighted images and 50% on T1 weighted images. All preoperative heavily T2 weighted images were compatible with operative findings. The optic chiasms were most commonly supero-posterior in pituitary adenomas, anterior (prefixed) in craniopharyngiomas and posterior in meningiomas. The optic nerves were commonly located superior or lateral to the tumours. However, parasellar meningiomas, off the midline, revealed the optic nerves in various locations, depending on the tumour origin. In such tumours, heavily T2 weighted images provided surgical information on the width of the working space through prechiasmal and/or optico-carotid spaces in the pterional approach. Spatial relation of the tumours to the lamina terminalis, anterior commissure and anterior communicating artery complex was clearly shown in craniopharyngioma patients, who underwent the anterior interhemispheric approach. CONCLUSION: Heavily T2 weighted MR images are useful in determining the location of optic pathways and surgical approach and in individual prediction of the anatomy for even large sellar and parasellar tumours.

Heavily T2 weighted MR assessment of fornical injury after anterior interhemispheric approach for large suprasellar tumors.

Fornical injury in transforaminal approach is well known. Its injury in the anterior interhemispheric approach (AIA) has been rarely highlighted. We report 2 cases with a large suprasellar tumor who underwent AIA. Postoperative heavily T2 weighted reversed (T2R) MR images demonstrated its unilateral injury. The clinical significance of symptom-free fornical injury after AIA is discussed. Cases 1 and 2 were a 15 year-old girl with a meningioma and a 49-year-old woman with a craniopharyngioma, respectively. They underwent AIA. Postoperative T2R images revealed unilateral fornical crus atrophy. They did not present associated memory deficits. Case 1 had the injury of both fornical column and anterior commissure. They were speculatively torn by intra-operative lateral retraction of the frontal lobes. Case 2 had unilateral atrophy of the mammillary body and postcommissural fornix, which were probably caused by ischemic damage related to surgical manipulation, since case 2 had an associated anterior thalamic infarct. During the operation for large suprasellar tumors, excessive laterally directed brain retraction should be avoided, since such manipulation may easily tear the overstretched anterior commissure and fornical column. Once we notice or suspect fornical injury on MR studies in cases of re-operation, we have to choose a surgical approach and operative manipulation to preserve an intact fornix. The MR evaluation of fornix should be included in the perioperative radiological assessment, since patients with unilateral fornical injury were free of memory disturbance, and T2R imaging is a useful MR sequence for depicting the anatomy related to the fornix.

Administration of granulocyte colony-stimulating factor induces hyporesponsiveness to lipopolysaccharide and impairs antigen-presenting function of peripheral blood monocytes.

OBJECTIVE: The incidence and severity of acute graft-vs-host disease after allogeneic transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) are not greater than those after conventional bone marrow transplantation despite infusion of more than one log greater number of donor T cells in PBSC. It has been postulated that monocytes from G-CSF-mobilized donors suppress alloreactivity of donor T cells. MATERIALS AND METHODS: We investigated the phenotype and function of monocytes in normal individuals receiving 10 microg/kg of G-CSF for 4 days. RESULTS: Monocytes were phenotypically and functionally different after G-CSF administration from steady-state monocytes. They were characterized by an increased CD14(+)CD16(+) subpopulation, reduced expression of HLA-DR, and diminished ability to produce tumor necrosis factor-alpha and interleukin-10 to lipopolysaccharide, compared with steady-state monocytes. These alterations were not replicated by culturing monocytes with G-CSF in vitro, suggesting an indirect effect of G-CSF. In addition, the antigen-presenting function of G-CSF-mobilized monocytes was impaired. CONCLUSION: Hyporesponsiveness of G-CSF-treated monocytes to lipopolysaccharide with regard to tumor necrosis factor-alpha production, together with impaired antigen-presenting function, may be responsible for the unexpectedly low incidence of graft-vs-host disease after G-CSF-mobilized PBSC transplantation.

Heavily T2-weighted MR imaging of white matter tracts in the hypothalamus: normal and pathologic demonstrations.

BACKGROUND AND PURPOSE: The MR appearance of white matter tracts in the hypothalamus and the role of the hypothalamus as a memory mechanism have not been sufficiently described in clinical settings. Heavily T2-weighted black-and-white reversed (T2R) images were assessed to reveal their visualization and clinical significance. METHODS: One hundred healthy subjects and three patients with hypothalamic lesions underwent fast spin-echo MR imaging to reveal the postcommissural fornix (PF) and mammillothalamic tract (MT). RESULTS: The PF was identifiable in axial and/or coronal sections in all healthy subjects. No remarkable asymmetry of its size or course was evident. Both anteroposterior and vertical dimensions ranged from 10.5 to 14 mm. The MT was visible in one or two axial sections above the mammillary body in 64% of healthy subjects and in a coronal section in 36%. Two patients with glioblastoma multiforme and lacunar infarct at the hypothalamus presented with anterograde amnesia; T2R imaging revealed involvement of both the PF and MT. The third patient had a suprasellar craniopharyngioma with PF injury sparing the MT resulting from surgical manipulation and was free of memory deficit. Anterograde amnesia was evident only when both the PF and MT were injured. CONCLUSION: T2R images have made a high rate of detection of the PF and MT possible and could provide a more detailed correlation of hypothalamic neuroanatomy and memory mechanism in clinical settings.

Hepatic graft-versus-host disease presenting as an acute hepatitis after allogeneic peripheral blood stem cell transplantation.

Hepatic graft-versus-host disease (GVHD) generally presents as cholestatic jaundice, and increased serum alkaline phosphatase (ALP) is followed by hyperbilirubinemia and clinical jaundice. Currently accepted standards for evaluating the clinical severity of GVHD are based not on serum aminotransferase levels but on the serum bilirubin level. We describe a 17-year-old Japanese female who had increased aminotransferases without cholestasis on day 23 after allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Liver biopsy revealed lymphocytic infiltration of the portal tracts and pericentral necrosis of the lobuli. The limiting plates were not clearly defined due to cellular infiltrates. There was periductal lymphocytic infiltration and vacuolization of the biliary epithelial cells with exocytosis, compatible with GVHD of cholangiohepatitic type. These findings indicate that acute hepatic GVHD may present as acute hepatitis and this should be included in the differential diagnosis for patients with increased aminotransferases after allogeneic stem cell transplantation.

Temporal profiles of the levels of endogenous antioxidants after four-vessel occlusion in rats.

Although it is known that development of lipid peroxidation after ischemia occurs predominantly in vulnerable regions, temporal profiles of antioxidants after ischemia have not been regionally elucidated. After reperfusion periods of 0, 3, 24, and 72 hours following 20 minutes of four-vessel occlusion (n = 6 in each group), the concentration of total glutathione (GSH) and the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) were assayed in the hippocampus, parietal cortex, striatum, thalamus, and brain stem. The levels of all antioxidants were unchanged in all regions without reperfusion; however, the concentration of total GSH significantly decreased in the hippocampus at 3 hours after the onset of reperfusion, and showed a maximum decrease in the hippocampus (68% of the sham-control level), parietal cortex (78% of the sham-control level), and striatum (76% of the sham-control level) after 24 hours of reperfusion. After 72 hours of reperfusion, these regions and the thalamus showed restoration and an increase in the total GSH concentration, respectively. The activities of SOD, GSH-Px, and catalase were stable during the reperfusion period, but the hippocampus showed significant increases in these enzyme activities and the parietal cortex and striatum showed significant increases in SOD activities at 72 hours after the onset of reperfusion. These results indicate that endogenous antioxidants take 72 hours for restoration in vulnerable regions after 20 minutes of four-vessel occlusion in rats.

High-dose chemotherapy with hematopoietic stem cell transplantation is effective for nasal and nasal-type CD56+ natural killer cell lymphomas.

CD56+ natural killer (NK) cell lymphomas occur frequently in the nasal and nasopharyngeal regions and carry a poor prognosis. We have studied seven cases with NK-cell lymphomas. These lymphomas showed the following immunophenotype: CD56+, CD2+, sCD3- and Epstein-Barr virus-encoded small RNAs (EBERs)+. Six patients had localized (stage I or II) disease involving the nasopharyngeal region, while one had stage III disease. One patient with stage I disease achieved a complete remission (CR) after treatment with involved-field irradiation, but subsequently relapsed and died. The remaining six patients received combination chemotherapy as primary treatment: five patients with localized stage I or II disease and one patient with advanced stage III disease. Responses to initial chemotherapy were generally poor. These six patients received a variety of salvage chemotherapy regimens, but never achieved a CR. Subsequently, four of six patients showed a highly aggressive clinical course and died of disseminated disease within 1 year from the diagnosis. Three of six patients received high-dose chemotherapy supported by syngeneic, autologous or allogeneic peripheral blood stem cell transplantation. Two of the three transplant patients achieved a CR and are now surviving in continuous CR. Our clinical experience suggests that myeloablative high-dose chemotherapy and bone marrow rescue by hematopoietic stem cell transplantation may be an effective salvage treatment modality for refractory NK-cell lymphomas and could be considered as a part of the initial therapy for these patients.

Treatment of asymptomatic unruptured intracranial aneurysms. A clinical decision analysis.

SUMMARY: The indication of preventive surgery for patients who harbor asymptomatic un ruptured intracranial aneurysms remains controversial. To evaluate the benefit of this treatment, we investigated the management outcome in 128 patients with 157 unruptured aneurysms. Surgery was planned in patients 70 years old or younger without serious systemic complications. A total of 77 patients underwent surgery including four endovascular interventions, and conservative management was chosen in 51 patients. There was no mortality and 6.5% morbidity as postoperative results, and no complication was found after endovascular treatment. Among the patients in conservative management, four patients suffered from subsequent rupture during the total follow-up period of 148 person-years. The annual rupture rate was estimated at 2.7%. According to the clinical decision analysis based on our data, preventive surgery is beneficial for a Japanese 70 years old or younger. However, the expected utility decreases if the rupture rate is set at 0.5% or 0.05%, posing a doubt about the benefit of the surgery. Decision analysis provides an aid for logical and objective choice in the management of unruptured aneurysms. The actual risk of rupture has a major impact on decision making in therapeutic strategy.

[Prevention of hepatitis B flare-up using lamivudine in a patient with non-Hodgkin's lymphoma after allogeneic bone marrow transplantation].

A 22-year-old man with non-Hodgkin's lymphoma (B-cell lymphoblastic lymphoma, Stage IVA) received chemotherapy and radiation therapy and achieved complete remission. He was admitted for allogeneic bone marrow transplantation (BMT) using a graft from his completely HLA-matched mother. Although he had HBV infection, allogeneic BMT was performed because he still had normal liver function and strongly requested the procedure. He developed both acute and chronic GVHD after the procedure, but showed no liver damage related to HBV. Treatment with lamivudine (150 mg/day) was started because the HBV-DNA level increased gradually after allogeneic BMT. Although the HBV-DNA then decreased gradually and there was no evidence of severe liver damage, the patient died following relapse of NHL. It seems that in this case, treatment of HBV with lamivudine may have prevented serious liver damage after allogeneic BMT. Therefore, allogeneic BMT may be done safely in patients with HBV infection if lamivudine is administered.