Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study.

BACKGROUND: Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. PATIENTS AND METHODS: Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score ≥1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), duration of response, progression-free survival and overall survival. RESULTS: All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9-31.4). Of the 13 patients with stable disease, 2 had stable disease lasting ≥24 weeks, for a disease control rate of 23.8% (95% CI 15.9-34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0-2.2), and median overall survival was 18.0 months (95% CI 12.9-23.0). CONCLUSIONS: Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02447003.

MR Imaging of the Superior Cervical Ganglion and Inferior Ganglion of the Vagus Nerve: Structures That Can Mimic Pathologic Retropharyngeal Lymph Nodes.

BACKGROUND AND PURPOSE: The superior cervical ganglion and inferior ganglion of the vagus nerve can mimic pathologic retropharyngeal lymph nodes. We studied the cross-sectional anatomy of the superior cervical ganglion and inferior ganglion of the vagus nerve to evaluate how they can be differentiated from the retropharyngeal lymph nodes. MATERIALS AND METHODS: This retrospective study consists of 2 parts. Cohort 1 concerned the signal intensity of routine neck MR imaging with 2D sequences, apparent diffusion coefficient, and contrast enhancement of the superior cervical ganglion compared with lymph nodes with or without metastasis in 30 patients. Cohort 2 used 3D neurography to assess the morphology and spatial relationships of the superior cervical ganglion, inferior ganglion of the vagus nerve, and the retropharyngeal lymph nodes in 50 other patients. RESULTS: All superior cervical ganglions had homogeneously greater enhancement and lower signal on diffusion-weighted imaging than lymph nodes. Apparent diffusion coefficient values of the superior cervical ganglion (1.80 ± 0.28 × 10-3mm2/s) were significantly higher than normal and metastatic lymph nodes (0.86 ± 0.10 × 10-3mm2/s, P < .001, and 0.73 ± 0.10 × 10-3mm2/s, P < .001). Ten and 13 of 60 superior cervical ganglions were hypointense on T2-weighted images and had hyperintense spots on both T1- and T2-weighted images, respectively. The latter was considered fat tissue. The largest was the superior cervical ganglion, followed in order by the retropharyngeal lymph node and the inferior ganglion of the vagus nerve (P < .001 to P = .004). The highest at vertebral level was the retropharyngeal lymph nodes, followed, in order, by the inferior ganglion of the vagus nerve and the superior cervical ganglion (P < .001 to P = .001). The retropharyngeal lymph node, superior cervical ganglion, and inferior ganglion of the vagus nerve formed a line from anteromedial to posterolateral. CONCLUSIONS: The superior cervical ganglion and the inferior ganglion of the vagus nerve can be almost always differentiated from retropharyngeal lymph nodes on MR imaging by evaluating the signal, size, and position.

Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial.

PURPOSE: The goal of chemotherapy for metastatic breast cancer (MBC) is to prolong survival and maintain health-related quality of life. This study aimed to evaluate long-term health status of patients with MBC who participated in the phase III randomized SELECT BC trial. METHODS: In the SELECT BC trial, patients were randomly allocated to the S-1 or taxane (paclitaxel or docetaxel) arm. Health status was assessed by EQ-5D at pre-treatment, 3 and 6 months after randomization, and every 6 months thereafter to the extent possible. Least square mean scores were assessed to compare EQ-5D index values between groups. Time to deterioration analysis was also performed by defining the minimally important difference of EQ-5D as 0.05 or 0.1. RESULTS: The number of patients for EQ-5D analysis was 175 and 208 in the taxane and S-1 arms, respectively. Least square mean EQ-5D index values up to 60 months were 0.741 (95 % CI [0.713-0.769]) in the taxane arm and 0.748 [0.722-0.775] in the S-1 arm. The EQ-5D index value during PFS up to 12 months in the S-1 was superior to the corresponding index value in the taxane (0.812 [0.789-0.834] vs. 0.772 [0.751-0.792], P = 0.009). Time to deterioration analysis also revealed that S-1 significantly delayed the deterioration of EQ-5D index value during the period before progression (P = 0.002 and 0.003). CONCLUSIONS: Our findings suggest that the EQ-5D index value was higher in patients treated with S-1 during first-line chemotherapy. Considering non-inferiority of S-1 in terms of OS, obtained quality-adjusted life years may be greater in the S-1 arm.

A phase II study of eribulin in Japanese patients with heavily pretreated metastatic breast cancer.

BACKGROUND: Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that recently gained Food and Drug Administration approval for late-line metastatic breast cancer (MBC). PATIENTS AND METHODS: In this single-arm, multicentre open-label phase II trial Japanese patients pretreated with an anthracycline and a taxane received 1.4 mg/m(2) eribulin mesylate (2- to 5-min i.v. infusion on days 1 and 8 of a 21-day cycle). The primary efficacy end point was overall response rate (ORR) by independent review. RESULTS: Patients (N = 80) had received a median of three prior chemotherapy regimens (range 1-5). ORR was 21.3% [95% confidence interval (CI) 12.9-31.8; all partial responses (PRs)], stable disease (SD) occurred in 30 patients (37.5%) and the clinical benefit rate (complete response + PR + SD ≥6 months) was 27.5% (95% CI 18.1-38.6). Median duration of response was 3.9 months (95% CI 2.8-4.9), progression-free survival was 3.7 months (95% CI 2.0-4.4) and overall survival was 11.1 months (95% CI 7.9-15.8). The most frequent treatment-related grade 3/4 adverse events were neutropenia (95.1%), leukopenia (74.1%) and febrile neutropenia (13.6%). Grade 3 peripheral neuropathy occurred in 3.7% of patients (no grade 4). CONCLUSIONS: Eribulin exhibited efficacy and tolerability in Japanese patients with heavily pretreated MBC.

The pro-apoptotic BH3-only protein Bim regulates cell cycle progression of hematopoietic progenitors during megakaryopoiesis.

SUMMARY BACKGROUND: The pro-apoptotic BH3-only protein Bim is recognized as a pivotal regulator of apoptosis induced by the depletion of cytokines. In the present study, we examined the role of Bim in megakaryopoiesis. METHODS: Megakaryocyte (MK) progenitors obtained from bim knockout (KO) mice were analyzed in vitro for liability to apoptosis after the depletion of cytokines, ability to differentiate into MKs and proliferation/cell cycle progression in response to thrombopoietin (TPO). The production of platelets in vitro was evaluated by assaying the formation of proplatelets in MKs. Megakaryopoiesis in vivo was observed in a mouse model of thrombocytopenia induced by injecting fluorouracil (5-FU). RESULTS: Bim-deficient CD34-/c-kit+/Sca-1+/Lineage- stem cells and MKs were highly resistant to apoptosis induced by cytokine depletion, suggesting that Bim is involved in the apoptotic process in both stem cells and MKs. As bim KO mice exhibited splenomegaly and thrombocytopenia, splenectomized mice were used for experiments in vivo. Platelet recovery after 5-FU-induced thrombocytopenia was significantly delayed in bim KO mice. Corresponding with this, numbers of MKs in the recovery phase bone marrow were significantly reduced in bim KO mice. Culture of c-kit+/Lineage- progenitors with TPO revealed that Bim-deficient cells poorly proliferate and differentiate into CD41+ cells in comparison with wild-type (WT) cells. However, once differentiated into MKs, these cells matured normally. Furthermore, cell cycle analyses demonstrated that transition from the G1 to the S phase was delayed in Bim-deficient stem cells. CONCLUSIONS: In the present study, we demonstrated that Bim plays a pivotal role in the regulation of cell cycle progression in hepatopoietic progenitors during megakaryopiesis.

Elucidation of structural requirements of mastoparan for mast cell activation-toward the comprehensive prediction of cryptides acting on mast cells.

Mastoparan, a toxic peptide from wasp venom, induces various biological functions including histamine release from rat peritoneal mast cells. Here we report that, for the activation of mast cells by mastoparan, at least two positively charged side chains are required on the hydrophilic side of the amphiphilic structure of the peptide. The present results are expected to be utilized for the bioinformatic and comprehensive identification of endogenous mast cell-stimulating cryptides.

Calcineurin-mediated dephosphorylation of c-Jun Ser-243 is required for c-Jun protein stability and cell transformation.

The proto-oncogene c-Jun plays an important role in regulating tumor progression. We previously reported that the serine/threonine phosphatase calcineurin (CaN, also called PP2B) dephosphorylates the C-terminus (Ser-243) of c-Jun, resulting in the increase in c-Jun and Sp1 interaction, and subsequent c-Jun-induced gene expression. Here, we demonstrate the interaction of c-Jun and CaN in the nucleus of living cells by fluorescence resonance energy transfer assay and that this interaction is mediated through the calmodulin-binding domain of CaN. Furthermore, c-Jun protein stability was altered by CaN-mediated dephosphorylation at the Ser-243 site of c-Jun. The half-life of the c-Jun mutant, c-Jun-S243A was longer than that of the wild-type c-Jun. Moreover, silencing of endogenous CaN expression led to increased c-Jun ubiquitination and decreased stability. In 46% of clinical cervical tissue samples obtained from patients with cervical cancer, enhanced c-Jun and CaN expression, as well as decreased phospho-Ser-243 expression levels were detected. Our results suggest that CaN stabilizes c-Jun by dephosphorylating c-Jun at Ser-243 to enhance its tumorigenic ability.

Hematopoietic stem cell transplantation for natural killer-cell lineage neoplasms.

Neoplasms of natural killer (NK)-lineage are rare. Their prognosis is generally poor except for cases of solitary nasal NK-cell lymphoma. The NK-cell Tumor Study Group performed a survey in Japan on patients diagnosed between 1994 and 1998. Of 228 patients selected for analysis, 40 underwent HSCT (15 allografts and 25 autografts). The underlying diseases were myeloid/NK cell precursor acute leukemia (n = 4), blastic NK-cell lymphoma (n = 11), aggressive NK-cell leukemia (n = 3), and nasal-type extranodal NK-cell lymphoma (n = 22). At the time of HSCT, 22 patients were in complete remission (CR), 11 were in relapse, and seven were primary refractory. All patients received myeloablative conditioning regimens including total-body irradiation. Sixteen died of disease progression, and six of treatment-related causes. Overall, 4-year survival was 39% with a median follow-up of 50 months; this was significantly better than that of patients who did not undergo HSCT (21%, P = 0.0003). For patients transplanted in CR, the 4-year overall survival was 68%, which was significantly better than that of patients who went into CR but did not undergo HSCT (P = 0.03). These findings suggest that the HSCT is a promising treatment strategy for NK-cell lineage.

Hippocampal synthesis of estrogens and androgens which are paracrine modulators of synaptic plasticity: synaptocrinology.

Hippocampal pyramidal neurons and granule neurons of adult male rats are equipped with a complete machinery for the synthesis of pregnenolone, dehydroepiandrosterone, testosterone, dihydrotestosterone and 17beta-estradiol. Both estrogens and androgens are synthesized in male hippocampus. These brain steroids are synthesized by cytochrome P450s (P450scc, P45017alpha and P450arom), hydroxysteroid dehydrogenases and reductases from endogenous cholesterol. The expression levels of enzymes are as low as 1/300-1/1000 of those in endocrine organs. Synthesis is dependent on the acute Ca(2+) influx upon neuron-neuron communication via NMDA receptors. Estradiol is particularly important because estradiol rapidly modulates neuronal synaptic transmission such as long-term potentiation via synaptic estrogen receptors. Xenoestrogens may also act via estrogen-driven signaling pathways.

Establishment and characterization of a cell line from a malignant fibrous histiocytoma of bone developing in a patient with multiple fibrous dysplasia.

PURPOSE AND METHODS: In order to provide material for genetic analysis of fibrous dysplasia (FD), a cell line designated GBS-1 was established from a secondary bone malignant fibrous histiocytoma (MFH) developing in a rib of a 44-year-old male polyostotic FD patient. RESULTS: The GBS-1 cells are characterized by a pleomorphic spindle cell morphology with abundant mucus production. On transplantation to nude mouse subcutis the cell line forms myxoid-spindle cell sarcomas with giant cells, the myxoid product being positive for periodic acid-Schiff (PAS) and alcian blue (Al-B) stains and completely digested by hyaluronidase, mimicking the original tumor. Chromosome and genetic analyses revealed multiple structural and numerical abnormalities of chromosomes with a large number of unidentifiable chromosomes and p53 mutation in exon 7 with LOH in the counterpart. CONCLUSIONS: Since cell lines for FD have hitherto not been available, the GBS-1 cells should prove useful for genetic analyses of FD and also MFH of bone origin.

Butenafine hydrochloride (Mentax) cream for the treatment of hyperkeratotic type tinea pedis and its transfer into the horny layer, with or without concomitant application of 20% urea ointment (Keratinamin).

Forty-five patients were divided into two groups: group I, 23 patients, treated with butenafine hydrochloride (Mentax) cream alone, and group II, 22 patients, treated with butenafine hydrochloride and 20% urea ointment (Keratinamin) to evaluate the usefulness of the treatments. We also measured the transfer of these drugs to the horny layer in some patients. The clinical improvement rate of dermatological symptoms (marked improvement + improvement) was 91.3% in group I, 100% in group II, with therapeutic effects evident earlier in group II than in group I. The mycological eradication rate was found to be 47.4% in group I, 50.0% in group II after 4 weeks of treatment, and 81.8 and 87.5% at 12 weeks thereaftcr. respectively, with no adverse reactions found. The clinical utility rate (markedly useful + useful) was 91.3% in group I and 86.4% in group II. These results demonstrate that application of butenafine hydrochloride alone was extremely effective for the treatment of hyperkeratotic-type tinea pedis and that combination application with urea ointment resulted in an earlier improvement of dermatological symptoms. The concentration of butenafine in the horny layer from healthy volunteers reached a steady state in both groups I and II at 2 weeks after the application, with a lower concentration found in group II (about 70 ng mg(-1)) than in group I (about 100 ng,mg(-1)). Although some variations in concentration were found in case by case, patients in whom the treatment was determined to be 'markedly effective and effective' showed the increase in concentration of the drug in the lesional horny layer to be directly proportional to the number of days of treatment, with a lower concentration found in group II than in group I. This trend was also seen in healthy volunteers.

Levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea--hypopnea syndrome.

To better understand how humans adapt to hypoxia, the levels of hemoglobin (Hb), serum erythropoietin (Epo), and vascular endothelial growth factor (VEGF) were measured in 106 patients with severe obstructive sleep apnea-hypopnea syndrome. The results indicated that temporal hypoxic stimulation increases Hb. Furthermore, a minor increase in Epo and a substantial increase in VEGF were found. The induction in patients with severe sleep apnea was greater than that reported in other types of hypoxia. (Blood. 2001;98:1255-1257)

Endoscopic treatment for laterally spreading tumors in the colon.

BACKGROUND AND STUDY AIMS: Laterally spreading tumors (LST) of the colon are best removed by endoscopic mucosal resection (EMR) as they extend laterally rather than vertically. Since they sometimes invade deeply into the submucosal layer, it is important to assess the depth of invasion endoscopically before treatment. In the present study, we examined the endoscopic features of a large number of LSTs in order to assess which features correlated with depth of invasion. MATERIALS AND METHODS: 257 LSTs removed at the National Cancer Center Hospital, Tokyo, between January 1988 and September 1998 were retrospectively analyzed. RESULTS: With univariate analysis, unevenness of nodules, presence of large nodules, size, histological type, and presence of depression in the tumor were significantly associated with depth of invasion. Multivariate analysis revealed that histological type and depression in the tumor were independent factors predicting massive submucosal invasion. When an LST showed: 1) even nodules without depression, or 2) uneven nodules without depression and less than 3 mm in diameter, the risk of massive submucosal invasion was 0 % (0/121) and 3.7 % (3/82), respectively. CONCLUSION: When LSTs meet the above endoscopic criteria, EMR should be the first-line treatment because of the low risk of massive submucosal invasion.

Radiographic evaluation of malignant fibrous histiocytoma affecting maxillary alveolar bone: a report of 2 cases.

OBJECTIVE: The purpose of this study was to evaluate the radiographic findings of malignant fibrous histiocytoma (MFH) and to discuss the contribution of these findings to a differentiation of MFH from other malignant tumors of the head and neck. STUDY DESIGN: Two cases of MFH of the maxillary sinus affecting the alveolar bone were evaluated radiographically and scintigraphically. RESULTS: We reported the following findings, which have only seldom been described: the presence of fairly well-demarcated bone destruction in the intraoral radiograph; the relatively smooth surface, uniform density, or no necrotic area of the tumor; in computed tomograph images showing the clear separation of the tumor from surrounding soft tissues; bone scintigraphs reflecting the periosteal reaction to tumor invasion; and lymphoscintigraphy of the metastatic lymph nodes. CONCLUSION: We evaluated the radiographic findings from 2 cases of MFH and describe findings that may aid in the differentiation of MFH. These radiographic features may help dentists differentiate MFH from other malignant tumors in the head and neck, although MFH is a rare disease and there are no radiographic findings that would indicate a specific diagnosis of MFH.

Elastofibroma in shoulder osteoarthritis: a theoretical concept of the etiology.

A case of unilateral, subscapular elastofibroma dorsi secondary to degenerative osteoarthritis in the ipsilateral glenohumeral joint is presented. A 69-year-old woman had experienced symptoms of osteoarthritis in the right shoulder since contracting septic arthritis when she was 7 years old. The patient noticed a soft tissue mass in the right subscapular region when she was 65 years old. The range of motion of the glenohumeral joint was severely restricted. Histopathologic examination of the excised mass revealed elastofibroma. The authors think the excessive scapulothoracic motion was important in formation of the lesion. This case indicates that elastofibroma is not a true neoplasm but a reactive lesion formed by repetitive minor trauma.

Detection of minimal residual disease in a patient having acute myelogenous leukemia with t(16;21)(p11;q22) treated by allogeneic bone marrow transplantation.

A 29-year-old woman having acute myelogeneous leukemia-M1 subtype with the chromosomal abnormality t(16;21)(p11;q22) is presented. Complete blood count at onset showed a hemoglobin level of 7.2 g/dl, a platelet count of 48 x 10(9)/l, and a white blood cell count of 161.2 x 10(9)/l with 99% blasts and 1% lymphocytes. Bone marrow aspiration revealed massive proliferation of blasts that were positive for CD13, CD33, CD34, CD56 and myeloperoxidase, and negative for other T-cell, B-cell and monocytic markers. After achieving complete remission following conventional chemotherapy, she received an HLA-matched bone marrow transplantation (BMT) from her sibling after conditioning with busulfan, etoposide and cyclophosphamide. However, 9 months later, the leukemia relapsed as a painful extramedullary mass in her left femur. In spite of intensive re-induction chemotherapy, she died of progressive disease and sepsis. Although we could not detect the TLS/FUS-ERG fusion transcripts by reverse transcriptase-polymerase chain reaction in pre-BMT remission phase, they were clearly detectable in bone marrow cells obtained 6 months after transplantation with no translocation detected by conventional cytogenetics. We consider that even high-dose chemotherapy with BMT may not be effective in the eradication of this type of leukemia, and that the detection of minimal residual disease possibly contributes to the better planning of the therapeutic strategy.

Stimulation of GATA-2 as a mechanism of hydrogen peroxide suppression in hypoxia-induced erythropoietin gene expression.

Hydrogen peroxide (H2O2) has previously been shown to inhibit the DNA binding activity of hypoxia inducible factor-1 (HIF-1), the accumulation of HIF-1alpha protein and erythropoietin (Epo) gene expression. Epo gene expression has been previously shown to be down-regulated through a GATA binding site at its promoter region. In this study, the effect of H2O2 on Epo gene expression under hypoxic conditions through a GATA transcription factor was investigated. Hypoxic induction was found to be inhibited upon the addition of H2O2, and this effect could be reversed through the addition of catalase. Hypoxic induction was found to be suppressed by co-transfection with a human GATA-2 cDNA expression plasmid. Transfection of Hep3B cells with a reporter gene bearing a mutation at the promoter GATA binding site was found to be only mildly affected by the addition of H2O2. Electrophoretic gel mobility shift assays (EMSAs), using the Epo promoter GATA site as a probe and the GATA-2 protein extracted from Hep3B cells, showed that addition of H2O2 enhanced the binding of GATA-2 while addition of catalase inhibited this binding. From these results, we conclude that H2O2 increases the binding activity of GATA-2 in a specific manner, thereby suppressing the activity of the Epo promoter and thus inhibiting Epo gene expression.

Phosphorylation of tau is regulated by PKN.

For the phosphorylation state of microtubule-associated protein, tau plays a pivotal role in regulating microtubule networks in neurons. Tau promotes the assembly and stabilization of microtubules. The potential for tau to bind to microtubules is down-regulated after local phosphorylation. When we investigated the effects of PKN activation on tau phosphorylation, we found that PKN triggers disruption of the microtubule array both in vitro and in vivo and predominantly phosphorylates tau in microtubule binding domains (MBDs). PKN has a catalytic domain highly homologous to protein kinase C (PKC), a kinase that phosphorylates Ser-313 (= Ser-324, the number used in this study) in MBDs. Thus, we identified the phosphorylation sites of PKN and PKC subtypes (PKC-alpha, -betaI, -betaII, -gamma, -delta, -epsilon, -zeta, and -lambda) in MBDs. PKN phosphorylates Ser-258, Ser-320, and Ser-352, although all PKC subtypes phosphorylate Ser-258, Ser-293, Ser-324, and Ser-352. There is a PKN-specific phosphorylation site, Ser-320, in MBDs. HIA3, a novel phosphorylation-dependent antibody recognizing phosphorylated tau at Ser-320, showed immunoreactivity in Chinese hamster ovary cells expressing tau and the active form of PKN, but not in Chinese hamster ovary cells expressing tau and the inactive form of PKN. The immunoreactivity for phosphorylated tau at Ser-320 increased in the presence of a phosphatase inhibitor, FK506 treatment, which means that calcineurin (protein phosphatase 2B) may be involved in dephosphorylating tau at Ser-320 site. We also noted that PKN reduces the phosphorylation recognized by the phosphorylation-dependent antibodies AT8, AT180, and AT270 in vivo. Thus PKN serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly.