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Histiocytic sarcoma (HS) is a rare malignancy showing morphologic and immunophenotypic features of histiocytes. HS has morphologic overlap with many other diseases, including various kinds of lymphomas. Gray zone lymphoma (GZL) is a rare B-cell lymphoma subtype characterized by overlapping features between diffuse large B-cell lymphoma and classic Hodgkin lymphoma. The histologic overlap with other diverse diseases of HS and the pathological diversity of GZL make it difficult to render a diagnosis. A 44-year-old woman who was initially diagnosed with HS was diagnosed with GZL after reexamination, including a genetic alteration test. After 6 cycles of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine, she achieved a complete response. Genomic alteration assessment may be useful for the accurate diagnosis of malignant lymphomas, which are difficult to diagnose, such as GZL.

Cholesteryl pullulan (CHP) is a novel antigen delivery system. CHP and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) antigen complexes (CHP-NY-ESO-1) present multiple epitope peptides to the MHC class I and II pathways. Adjuvants are essential for cancer vaccines. MIS416 is a non-toxic microparticle that activates immunity via the nucleotide-binding oligomerization domain 2 (NOD2) and TLR9 pathways. However, no reports have explored MIS416 as a cancer vaccine adjuvant. We conducted a first-in-human clinical trial of CHP-NY-ESO-1 with MIS416 in patients with NY-ESO-1-expressing refractory solid tumors. CHP-NY-ESO-1/MIS416 (μg/μg) was administered at 100/200, 200/200, 200/400 or 200/600 (cohorts 1, 2, 3 and 4, respectively) every 2 weeks for a total of 6 doses (treatment phase) followed by one vaccination every 4 weeks until disease progression or unacceptable toxicity (maintenance phase). The primary endpoints were safety and tolerability, and the secondary endpoint was the immune response. In total, 26 patients were enrolled. Seven patients (38%) continued vaccination in the maintenance phase. Grade 3 drug-related adverse events (AEs) were observed in six patients (23%): anorexia and hypertension were observed in one and five patients, respectively. No grade 4–5 drug-related AEs were observed. Eight patients (31%) had stable disease (SD). Neither augmentation of the NY-ESO-1-specific IFN-γ-secreting CD8+ T cell response nor an increase in the level of anti-NY-ESO-1 IgG1 was observed as the dose of MIS416 was increased. In a preclinical study, adding anti-PD-1 monoclonal antibody to CHP-NY-ESO-1 and MIS416 induced significant tumor suppression. This combination therapy is a promising next step. Electronic supplementary material The online version of this article (10.1007/s00262-020-02483-1) contains supplementary material, which is available to authorized users.

Background: Although weekly paclitaxel and trastuzumab is generally considered to be less cardiotoxic than an anthracycline regimen, low baseline left ventricular ejection fraction (LVEF) of ≤55%, hypertension, and high body mass index (BMI) have been reported as risk factors for cardiotoxicity. Without these risk factors, the incidence of cardiotoxicity is expected to be minimal. Method: We retrospectively reviewed the medical records of 86 patients with HER2-positive, node-negative breast cancer between February 2012 and December 2018. Patients were selected for this study according to the following criteria: (1) patients were administered weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by trastuzumab; (2) baseline LVEF was 60% or more; (3) echocardiography was performed before, during, and at the end of treatment; (4) no hypertension or well-controlled with medication; and (5) BMI was < 30. We investigated the occurrence of cardiotoxicity. A decline in LVEF was defined as a decrease of 15% or more from baseline, or < 50% decrease in LVEF.Results: A total of 40 patients fulfilled the eligibility criteria. The median age was 55.5 (35 to 72) and median baseline LVEF was 68% (60 to 77). The median number of echocardiograms was five (3-7). Out of 40, trastuzumab were completed in 39. Among the 39 patients, no symptomatic congestive heart failure or asymptomatic LVEF decline was observed. Conclusion: In our study, no cardiotoxicity was observed in paclitaxel and trastuzumab. Assessment of cardiac function during treatment may be simplified in patients without risk factors for cardiotoxicity.

// Yasutaka Tono 1, 2 , Mikiya Ishihara 2 , Yoshihiro Miyahara 3 , Satoshi Tamaru 2 , Hiroyasu Oda 2 , Yoshiki Yamashita 2 , Isao Tawara 1 , Hiroaki Ikeda 3, 4 , Hiroshi Shiku 3 , Toshiro Mizuno 2 and Naoyuki Katayama 1, 2 1 Department of Hematology and Oncology, Mie University Graduate School of Medicine, 514-8507 Mie, Japan 2 Department of Medical Oncology, Mie University Hospital, 514-8507 Mie, Japan 3 Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, 514-8507 Mie, Japan 4 Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, 852-8523 Nagasaki, Japan Correspondence to: Mikiya Ishihara, email: mishihara@clin.medic.mie-u.ac.jp Keywords: breast cancer; eribulin mesylate; HER2-positive; trastuzumab; pertuzumab Received: May 09, 2017 Accepted: February 07, 2018 Epub: February 16, 2018 Published: March 13, 2018 ABSTRACT The standard treatment for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is the triple combination of pertuzumab, trastuzumab and docetaxel, but some patients cannot tolerate taxane. To explore a non-taxane triple therapy, we conducted a feasibility study of pertuzumab, trastuzumab and eribulin mesylate (PTE) therapy for previously treated advanced HER2-positive breast cancer with analyses of quality of life and biomarkers. Ten patients were enrolled, two of whom had a history of docetaxel allergy. The median number of prior regimens was 3. The most common Grade 3 toxicities were leukopenia (70%) and neutropenia (70%). Grade 4 or 5 adverse events were not observed. An improving trend for the Functional Assessment of Cancer Therapy-Breast (FACT-B) score at 3 months was observed. Eight cases were included in the biomarker analysis. The peripheral CD8+ T cell/ CD4+Foxp3+ regulatory T cells (Tregs) ratio was significantly increased ( p = 0.039). The frequency of peripheral Tregs was associated with the trastuzumab trough concentration ( p = 0.019). In a non-clinical analysis, Eribulin mesylate significantly inhibited Ser473 Akt phosphorylation in PIK3CA wild-type cells and mutated cells. These results suggest that PTE therapy is a feasible and promising option for advanced HER2-positive breast cancer. Further investigation is warranted.

[Introduction] The triple therapy of pertuzumab, trastuzumab and taxanes (docetaxel or paclitaxel) is coming into widespread use, because of the beneficial effects on HER2 positive breast cancer. However, we don't have enough information about the efficacy and safety of other agents with trastuzumab and pertuzumab (TP). We studied triple therapy of pertuzumab, trastuzumab and eribulin (PTE) for advanced HER2 positive breast cancer to assess the efficacy, safety and QOL prospectively (UMIN000012018). [Patients and methods] Responses were assessed by RECIST criteria v1.1. Adverse events (AEs) were graded according to CTCAE v4.0. Patients with advanced HER2 positive breast cancer were treated with pertuzumab (840 mg loading then 420 mg, day 1), trastuzumab (8 mg/kg loading then 6 mg/kg, day 1), and eribulin (1.4 mg/m2, day 1 and 8) every 3 weeks. Dose reduction was allowed when patients developed febrile neutropenia, grade 3-5 non-hematologic toxicity or skipped day 8 eribulin administration because of neutrophil count [Results] Ten patients were enrolled. Median age of patients was 60 years-old (35-75). Median number of prior chemoregimen for metastatic disease was 3 (0-5). Two patients had a history of docetaxel allergy. Median number of PTE cycle was 6 (3-12). Eight patients reduced eribulin doses 1.4 mg/m2 to 1.1 mg/m2 because of AEs (2 patients), skipped day 8 eribulin (4 patients), or physician's choice (2 patients). One complete response, 1 partial response and 5 stable disease were achieved at 3 months. Two patients (1 CR and 1 SD) stopped eribulin and received TP as maintenance therapy. At 3 months, all 3 patients with progressive disease developed brain metastasis. Two patients had extracranial progressive lesions, but 1 patient had partial response for extracranial disease. The common treatment-related AEs were leukopenia, neutropenia, lymphopenia diarrhea, hypokalemia and stomatitis. Grade 3 AEs were leukopenia (7 patients), neutropenia (8 patients), lymphopenia (2 patients), febrile neutropenia (1 patient), hypokalemia (1 patient) and peripheral neuropathy (1 patient). Grade 4/5 AEs were not observed. Nine patients could be assessed QOL. FACT-B TOI, FACT-G and FACT-B total score had a tendency to be improved at 3 months. [Conclusion] The PTE therapy showed appropriate clinical effect for extracranial lesions and maintained QOL of patients with advanced HER2 positive breast cancer. It may be a choice for patients who have taxane-resistant diseases or a history of taxane allergy. Many patients needed to reduce eribulin dosage. When the PTE therapy is referred to advanced HER2 positive breast cancer patients as a palliative chemotherapy, eribulin (1.1mg/m2) might be a reasonable dosage. Citation Format: Ishihara M, Tamaru S, Oda H, Yamashita Y, Tono Y, Mizuno T, Katayama N. A pilot study of pertuzumab, trastuzumab and eribulin for patients with advanced HER2 positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-21.

Although immunotherapy has been demonstrated to be promising in triple-negative (TN) breast cancer (BC), most BC cases are classified as non-TN. To enrich the responders for immunotherapy regardless of their subtypes, classification based on tumor-infiltrating lymphocyte (TIL) levels and programmed death ligand-1 (PD-L1) status may be useful. However, this classification has not been fully applied to BC. Furthermore, suppressive subsets in the local tumor microenvironment, such as tumor-associated macrophages (TAMs), which promote tumor progression, cannot be ignored to overcome immunotherapy resistance. The aims of the present study were to classify primary BC cases based on the TIL levels and PD-L1 status, and to identify suppressive immune subsets in each categorized group. A retrospective analysis of 73 patients with invasive BC was performed. The frequency of TILs was evaluated in HE-stained slides (10% cutoff), and PD-L1 levels (SP142; 1% cutoff), as well as immune subsets (CD3+, CD8+, FOXP3+, CD20+, CD68+ and CD204+ cells) were assessed using immunohistochemistry. It was revealed that 22% (16/73) of the tumors were categorized as TIL+PD-L1+, of which 69% (11/16) were TN type. By contrast, 66% (48/73) of the tumors were categorized as TIL−PD-L1−, of which 77% (37/48) were HR+ and HER2− types. The number of CD204+ M2-type macrophages was significantly associated with high histological grade (P=0.0246) and high Ki-67 (P=0.0152), whereas CD68+ macrophages were not associated with these factors. Furthermore, CD204+ macrophages and FOXP3+ Tregs accumulated in 88% (14/16) and 63% (10/16) of TIL+PD-L1+ tumors, respectively, compared with 20.8% (10/48) and 27.1% (13/48) of TIL−PD-L1− tumors. In conclusion, 22% of BC tumors were classified as TIL+PD-L1+ (69% were TN), which were enriched with suppressive immune subsets. These cell types may serve as potential novel immunotherapeutic targets.

Anagrelide is a cytoreductive agent for essential thrombocythemia and its common side effects are anemia, headache, palpitation, diarrhea, and fluid retention. However, severe pulmonary adverse effects are rare. A 66-year-old Japanese man with essential thrombocythemia presented with hemoptysis 2 months after starting anagrelide treatment. Interstitial pneumonia was diagnosed based on physical and radiographic findings. Discontinuation of anagrelide and institution of corticosteroids resulted in the improvement of interstitial pneumonia. Severe lung injury associated with anagrelide is a rare but an important adverse event that must be addressed when treating interstitial pneumonia.

e15176Background: Complexes of Cholesteryl pullulan and NY-ESO-1 antigen (CHP-NY-ESO-1) present multiple epitope peptides to both the MHC class I and class II pathways. MIS416 is a non-toxic microp...

The usefulness of lupus anticoagulant (LA) and several antibodies for predicting thrombosis was assessed in patients with idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), lupus like disease (LLD), recurrent abortion and primary antiphospholipid syndrome (APS). LA was measured using the diluted Russell Viper Venom test (DRVVT) and the diluted prothrombin time (dPT). In healthy volunteers, the median (range) of the DRVVT and dPT ratio were 0.97 (0.88 - 1.08) and 1.05 (0.85 - 1.29), re- spectively. The positive percent of dPT ratio was high in patients with ITP, SLE, recurrent abortion and primary APS. The sensitivity for thrombosis was highest for the dPT ratio and the specificity for thrombosis was highest for the DRVVT ra- tio. The sensitivity and the Odd's ratio for both the dPT and DRVVT ratio were high. A positive predictive value in DRVVT and a negative predictive value in dPT were high. The receiver operating characteristic (ROC) curve analysis in- dicates that the dPT ratio might be more useful for predicting thrombosis than the DRVVT ratio. The DRVVT and dPT ratios are useful for both the diagnosis of APS as well as predicting thrombosis.

A 36-year-old woman complained of a mass on the sole of her foot in February 200X. She was diagnosed with extranodal NK/T-cell lymphoma, nasal type (ENKL) by skin biopsy. Because the lesion was localized on the subcutaneous tissue of the sole, she was treated with RT/2/3DeVIC, resulting in a complete response (CR). In March of the following year, PET/CT showed significant uptake and mucosal thickening in the right nasal cavity, and a mucosal biopsy confirmed ENKL infiltration. Because the lesion was localized in the nasal cavity, she was re-treated with RT/2/3DeVIC, with a focus on local control, and she achieved a second CR. She subsequently received allogeneic hematopoietic stem cell transplantation in the hope of preventing systemic relapse. She has remained in CR for four years since the transplantation. Our case suggests that allogeneic hematopoietic stem cell transplantation to be a potentially promising approach to curative treatment for recurrent ENKL in younger patients. As nasal lesions may subsequently appear during the course of primary non-nasal ENKL, ongoing meticulous evaluation for nasal lesions is important.

Proteinase 3 (PR3) expression on neutrophils was examined in rheumatoid arthritis (RA) patients before and after antitumor necrosis factor (TNF)-α therapy. Membrane PR3 expression from patients with either an infection or RA significantly increased. Membrane PR3 expression on neutrophils from RA patients treated with infliximab (anti-TNF-α antibody) therapy was less than in those without such treatment in a resting state, but the expression later increased after stimulation in vitro. Membrane PR3 expression increased because of the stimulation of TNFα, whereas it was significantly suppressed by plasma or α1-proteinase inhibitor. The condition of patients with RA improved after treatment with infliximab. Membrane PR3 expression on neutrophils in RA patients was downregulated by infliximab. As a result, PR3 might play an important role in the neutrophil-mediated inflammatory reaction in patients with either RA or an infection.

Background For the prevention of nausea/vomiting during anthracyline/cyclophosphamide (CPA) therapy for breast cancer, the use of aprepitant (AP) combined with serotonin antagonist and dexamethasone is recommended. It has been reported that AP does not influence AUC's of 4-hydro-cyclophosphamide, an active metabolite of CPA and DCE, a CPA-metabolite causing nephrotoxicity. Although, in the previous clinical reports for anthracyline/CPA, the toxicities were not significant in patients who were given AP, compared with those without AP, we have experienced several cases of severe hyponatremia probably caused by AP. Occurrence of hyponatremia during chemotherapy might be an issue to be cautious. Methods We investigated serum levels of Na in 67 breast cancer patients who received CPA-combined therapy with the use of AP or not. They all received 600 mg/m2 of CPA combined with either of doxorubicine, epirubicin, or docetaxel. Their prior electrolytes were to be within the normal range. In the first cycle, we evaluated serum Na levels before the CPA start and those of 24 h after. We defined a serum Na level lower than 135 mEq/l as ‘hyponatremia’. Results The background between the two groups, with AP and without AP, was comparable, in whom the prior Na levels were 140.0 ± 1.97 and 140.1 ± 1.88 mEq/l, in the AP group and in the non-AP group, respectively. The chemotherapies including CPA, the clinical stages, the uses of serotonin-receptor antagonist and dexamethasone were comparable between the two groups. Hyponatremia occurred in 11 of 42 (26.2%) patients in the AP group, whereas 2 of 25 patients (8.0%) in the non-AP group. Since the rate in the non-AP group was comparable with the previous reports, hyponetremia seemed to occur frequently in the AP group. The average Na level at 24 h after chemotherapy was 136.429 ± 3.94 mEq/L in the AP group and 138.68 ± 3.05 mEq/l in the non-AP group, respectively. Among 11 patients who developed hyponateremia, they were resolved within 48 h without any treatments in 10 patients and only one needed the Na replacement. The patient did not develop hyponatremia without using AP in the third cycle. Conclusions According to our cohort study, AP might frequently cause hyponatremia in the CPA-combined chemotherapy.

Background For prevention of emesis during anthracyline (A)/cyclophosphamide(CPA) therapy for breast cancer, use of aprepitant(AP) combined with serotonin receptor antagonist(5HT3) and dexamethasone(DEX) is recommended. AP, known to function as a CYP3A4 inhibitor, has been reported to interfere with metabolism of chemotherapeutic drugs. It has been also reported that AP does not influence the AUC's of 4-OH and DCE. Although, in the previous clinical reports for AC, the toxicities were not significant in patients who were given AP, compared to those without AP, we have experienced a cases of severe hyponatremia probably related to AP. Thus, we investigated an impact of AP on Na metabolism during chemotherapy using CPA for breast cancer. Material and methods We investigated serum levels of Na in primary breast cancer patients who received CPA-combined therapy with the use of AP as anti-emesis, or not. They all received 600mg/m2 of CPA combined with either of anthracycline or docetaxel. Their ages were to be less than 65 years, and their GFR's were more than 60 ml/min/1.73m2. Their prior electrolytes were to be within normal range. In the first cycle, we evaluated serum Na levels before the CPA start and that at 24 hours after. We defined serum Na level lower than 135 mEq/L as “hyponatremia” based on previous study. We enrolled 81 patients, in whom 52 were given AP and 29 were without AP, between December 2010 and April 2012. Results The background between the two groups, with AP and without AP, were comparable, in whom the median ages were 53.0(33-64) and 53.2(38-65), and the prior Na levels were139.84 ± 1.89 mEq/L, and 140.25 ± 1.82 mEq/L, in the AP-group and in non-AP-group, respectively. The uses of 5HT3 and DEX were similar between the two groups. The incidence of CPA-induced hyponatremia was significantly higher in AP-group than in non-AP-group (26.9% v 6.9%; P =0.04). The average Na level at 24 hours after chemotherapy was 136.32 ± 3.73 mEq/L in AP-group, and 138.60 ± 2.92 mEq/L in non-AP-group. Among 14 patients who developed hyponateremia in AP-group, they were resolved without any intervention in 13, and one needed Na replacement. The patient did not develop hyponatremia without AP in the third cycle. Conclusions According to our cohort study, AP cause hyponatremia more frequently in the CPA-combined chemotherapy. Disclosure All authors have declared no conflicts of interest.

e19546 Background: For prevention of nausea/vomiting during anthracyline/cyclophosphamide (CPA) therapy for breast cancer, use of aprepitant (AP) combined with serotonin antagonist and dexamethasone is recommended. It has been reported that AP does not influence AUC’s of 4-hydro-cyclophosphamide, an active metabolite of CPA, and DCE, a CPA-metabolite causing nephrotoxicity. Although, in the previous clinical reports for anthracyline/CPA, the toxicities were not significant in patients who were given AP, compared to those without AP, we have experienced several cases of severe hyponatremia probably caused by AP. Occurrence of hyponatremia during chemotherapy might be an issue to be cautious. Methods: We investigated serum levels of Na in 67 breast cancer patients who received CPA-combined therapy with the use of AP, or not. They all received 600mg/m2 of CPA combined with either of doxorubicine, epirubicin, or docetaxel. Their prior electrolytes were to be within normal range. In the first cycle, we evaluated serum Na levels before the CPA start and those of 24 hours after. We defined a serum Na level lower than 135 mEq/L as “hyponatremia”. Results: The background between the two groups, with AP and without AP, were comparable, in whom the prior Na levels were 140.0 ±1.97 mEq/L, and 140.1 ±1.88 mEq/L, in the AP- and in non-AP-group, respectively. The chemotherapies including CPA, the clinical stages, the uses of serotonin-receptor antagonist and dexamethasone were comparable between the two groups. Hyponatremia occurred in 11 patients out of 42 (26.2%) in AP-group, whereas 2 patients in 25 (8.0%) in non-AP-group. Since the rate in non-AP-group was comparable to the previous reports, hyponetremia seemed to occur frequently in AP-group. The average Na level at 24 hours after chemotherapy was 136.429 ±3.94 mEq/L in AP-group, and 138.68 ±3.05 mEq/L in non-AP-group, respectively. Among 11 patients who developed hyponateremia, they were resolved within 48 hours without any treatments in 10 patients, and only one needed Na replacement. The patient did not develop hyponatremia without using AP in the third cycle. Conclusions: According to our cohort study, AP might frequently cause hyponatremia in the CPA-combined chemotherapy.