[Analysis of Prognostic Factors Considering Absolute Lymphocyte Count of Metastatic Breast Cancer Patients with Eribulin Mesylate Therapy-A Retrospective Study in a Single Institution].

Recently, a study for eribulin mesylate(ERI), which is a useful drug for metastatic and recurrent breast cancer, reported that the absolute lymphocyte count(ALC)before administration is a useful prognostic factor. We retrospectively examined whether the results were reproducible in the patients with ERI. We examined the effect of ERI on the overall survival(OS)in 21 patients with HER2-negative metastatic and recurrent breast cancer who underwent treatment with ERI at our hospital. The clinical benefit ratio(CBR)was 57.1%. The median time to treatment failure(TTF)was 5.8 months and median OS was 19.9 months, showing a positive correlation between the TTF and OS. The factors that significantly prolonged the OS in univariate analysis were the TTF(<3 months vs ≥3 months, p<0.001), NLR(<3 vs ≥3, p=0.037), and ALC(<1,000/ µL vs ≥1,000/µL, p=0.008). In the multivariate analysis, TTF and ALC were the prognostic factors. The ERI outcome at our institution was good regardless of the subtype. The results of the multivariate analysis showed that TTF and ALC were factors that prolonged OS, and patients who received ERI for >3 months had good OS. Long-term administration of ERI was assumed to affect the immune microenvironment and prolong OS. Additionally, our data showed that the lymphocyte count before ERI administration is a simple and useful prognostic factor.

A rare case of synchronous multiple primary malignancies of breast cancer and diffuse large B-cell lymphoma that responded to multidisciplinary treatment: a case report.

BACKGROUND: Multiple primary malignancies of breast cancer and diffuse large B-cell lymphoma (DLBCL) are rare. Here, we report a case of advanced breast cancer and DLBCL managed with multidisciplinary therapy preceded by surgery with a successful outcome. CASE PRESENTATION: During a medical examination, a 71-year-old woman was diagnosed with a right breast mass, enlarged lymph nodes throughout the body, and a splenic tumor. The results of the clinical examination and imaging were suggestive of widely spread breast cancer with lymph node metastasis and malignant lymphoma with systemic metastasis. The histological evaluation of the biopsied breast tissue revealed human epidermal growth factor receptor 2 (HER2)-positive breast cancer, whereas the histological evaluation of the excised inguinal lymph node revealed DLBCL. 18F-FDG PET/computed tomography was performed, and it was determined that both breast cancer and DLBCL were in an advanced stage. Thus, mastectomy was performed, and the axillary lymph nodes showed mixed metastasis of breast cancer and DLBCL. Soon after, the R-CHOP therapy was initiated (375-mg/m2 rituximab, 2-mg/m2 vincristine, 50-mg/m2 doxorubicin, 750-mg/m2 cyclophosphamide, and 125-mg methylprednisolone). After irradiation of the spleen, trastuzumab was administered for 1 year. CONCLUSIONS: We experienced a case of combined breast cancer and DLBCL, which was difficult to treat because both were in advanced stages. Thorough staging of the malignancy and discussion by a multidisciplinary team are necessary to determine the optimal treatment strategy.

Clinical Evaluation of Endoscopic Bronchial Occlusion with an Endobronchial Watanabe Spigot for the Management of Intractable Pneumothorax, Pyothorax with Bronchial Fistula, and Postoperative Air Leakage.

Objective The present study aimed to evaluate the clinical effectiveness of endoscopic bronchial occlusion (EBO) with endobronchial Watanabe spigots (EWSs) for the management of prolonged pulmonary air leaks, such as intractable pneumothorax, pyothorax with bronchial fistula, and postoperative air leakage. Methods This was a retrospective study. Between April 2005 and March 2018, we recruited 21 patients with intractable pneumothorax (10 cases), pyothorax with bronchial fistula (7 cases), and postsurgical pulmonary fistula (4 cases) in whom appropriate drainage for 2 weeks had been unsuccessful and who were unsuitable for surgery. An EWS was inserted using a flexible bronchoscope via an endotracheal or a tracheostomy tube. Results The mean number of sessions with EWS procedures was 1.94, and the mean number of inserted EWS per patient was 6.5. In addition to EWS procedures, pleural washing and pleural adhesion therapy were performed in all cases with pyothorax, whereas pleural adhesion therapy was performed in three patients with pneumothorax. The successful treatment rate was 85.7%. Reduction of air leakage was observed in 19/21 patients. The mean duration of reduction of air leaks was 4.1 days (median, 1; range, 0-24 days) following EWS procedures. The mean duration from tube insertion to chest tube removal was 43.4 days (median, 29; range, 16-105 days). Complications included spigot migration and infection (aspergillosis); no complications caused significant mortality. Conclusion Performing EBO using an EWS appears to be a reasonable option for the management of intractable pneumothorax, pyothorax with pulmonary fistula, and postoperative air leakage.

Bronchial mucoepidermoid carcinoma, recurrent asthmatic symptoms, and pneumonia presenting in pregnancy.

We report the case of a 37-year-old pregnant Japanese woman (34th week of gestation) with a left main bronchus mucoepidermoid carcinoma. She had left lower lung pneumonia episodes for eight weeks that had been associated with bronchial asthma. Bronchoscopy revealed a membranous endobronchial tumour obstructing most of the left main bronchus. We delivered the baby without any problems by caesarean section, followed by tumour cauterization using a rigid bronchoscope under general anaesthesia. After that, we performed a sleeve resection of the main left bronchus. At one-year follow-up, the patient was disease-free and her baby was growing well.

Clinical Features and Treatment Outcomes of 81 Patients with Aggressive Type Adult T-cell Leukemia-lymphoma at a Single Institution over a 7-year Period (2006-2012).

OBJECTIVE: Despite the remarkable advances in chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), adult T-cell leukemia-lymphoma (ATL) is still associated with a high mortality rate. It is therefore essential to elucidate the current features of ATL. METHODS: We retrospectively analyzed 81 patients with aggressive type ATL at our institution over a 7-year period based on Shimoyama's diagnostic criteria. RESULTS: Eighty-one patients with a median age of 67.5 years were classified as having acute (n=47), lymphoma (n=32), or chronic type (n=2) ATL. They were initially treated by either palliative therapy (n=25) or systemic chemotherapy [n=56; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (n=25)/vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP)-doxorubicin, ranimustine, and prednisone (AMP)-vindesine, etoposide, carboplatin, and prednisone (VECP) therapy (VCAP-AMP-VECP) or CHOP-VMMV therapy (n=31)], and showed median survival durations of 16 and 277 days, respectively. Subsequent to the initial treatment, HSCT (n=6) was performed for certain patients, thus revealing that two-thirds (n=4) relapsed, and one-third (n=2) survived for 131 days and 203 days, respectively. The relapsed ATL patients were treated with conventional salvage therapy (n=29) or anti-CC chemokine receptor 4 antibody (mogamulizumab) (n=3). The patients treated with mogamulizumab demonstrated complete response (2) and partical response (1) with short duration periods of 82 days, 83 days, and 192 days, respectively. Among the five long-term survivors (>5 years) who received chemotherapy, most showed a low and intermediate risk according to the ATL prognostic index. CONCLUSION: In our study, the overall survival of ATL remains poor due to the advanced age of the patients at diagnosis, a high proportion of patients receiving palliative therapy, and a small proportion of long-term survivors receiving chemotherapy and undergoing HSCT. This study illustrates the current clinical features, treatment strategies, and outcomes in clinical practice.

Effects of recombinant human soluble thrombomodulin treatment for disseminated intravascular coagulation at a single institution--an analysis of 62 cases caused by infectious diseases and 30 cases caused by hematological diseases.

OBJECTIVE: Disseminated intravascular coagulation (DIC) is a clinical condition with high mortality that is characterized by the systemic activation of coagulation pathways resulting in multiple organ failure. Although no standard treatment for DIC has been established, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. METHODS: To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 92 DIC patients who were treated with rTM at Miyazaki Prefectural Hospital over a 4-year period (62 patients had infectious diseases and 30 patients had hematological diseases). A diagnosis of DIC was made based on the diagnostic criteria of the Japanese Association for Acute Medicine (JAAM) and Japanese Ministry of Health and Welfare (JMHW) for infectious diseases and hematological diseases, respectively. In addition to treating the underlying disease, rTM was administered for six consecutive days. RESULTS: In this study, 49 of the 92 DIC patients (53.3%) experienced resolution of DIC seven days after administration (46.8% patients with infectious disease and 66.7% with hematological disease). A higher survival rate was observed after a 28-day observation period in 69 of the 92 patients (75.0%) (72.6% of the patients with infectious disease and 80.0% of the patients with hematological disease). A lower DIC score at the initiation of rTM treatment was closely related to a higher rate of resolution of DIC. CONCLUSION: Our findings indicate that rTM therapy is an effective, safe and feasible treatment for DIC patients. Furthermore, making an accurate and early diagnosis of DIC and providing subsequent immediate treatment with rTM may improve the resolution of DIC.

Successful surgical treatment for pulmonary crystal-storing histiocytosis following the onset of gastric non-hodgkin lymphoma.

Crystal-storing histiocytosis is a rare clinical entity characterized by an increase in the number of abnormal histiocytes accompanied by accumulation of crystallized immunoglobulins. We describe the case of an 80-year-old man who presented with crystal-storing histiocytosis of the lung 13 years after receiving a diagnosis of gastric non-Hodgkin lymphoma (NHL ; clinical stage, Lugano IA). After wedge resection of the left upper lobe, the histological findings showed crystal-storing histiocytosis with CD68(+), some small to medium lymphoid cells with CD79a(+) with κ(+(weekly)) and λ(-), and some plasma cells with CD138(+), and rearrangement of the immunoglobulin heavy chain. Based on the nonrecurrent gastric NHL, small B-cell population, and failure to detect the same clone by polymerase chain reaction analysis, our case was classified as pulmonary localized crystal-storing histiocytosis without underlying lymphoproliferative or plasma cell disorder. The findings of minor B-cell populations harboring a heavy chain rearrangement with slight light-chain restriction (κ > λ) may be related to the pathogenesis of crystallogenesis and crystal-storing histiocytosis. Moreover, surgical treatment may be an effective therapeutic option for solitary crystal-storing histiocytosis.

Successful treatment of immunodeficiency-associated EBV-negative lymphoproliferative disorders in rheumatoid arthritis by methotrexate withdrawal and prevention of its relapse by rituximab administration.

Immunodeficiency-associated lymphoproliferative disorders (LPD) in rheumatoid arthritis are a rare, aggressive, and life-threatening clinical entity. We describe a 60-year-old man who had rheumatoid arthritis that was treated with methotrexate. Eight months after the treatment, the case was diagnosed as Epstein-Barr virus-negative LPD (diffuse large B-cell lymphoma) with abdominal bulky mass and clinical stage IVB at high risk in the international prognostic index. Immediate withdrawal of methotrexate led the patient to achieve complete remission, and 8 subsequent courses of rituximab treatment for the prevention of relapse kept the patient disease-free for 29 months. Our case suggests that these treatments may be an effective, safe, and feasible strategy for immunodeficiency-associated LPD in rheumatoid arthritis.

Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells.

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Recently, we have shown that insulin-like growth factor-I and serum-derived growth factors stimulate VEGF expression in neuroblastoma cells via induction of hypoxia-inducible factor-1alpha (HIF-1alpha). Because another marker of poor prognosis in neuroblastoma tumors is high expression of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor, TrkB, we sought to evaluate the involvement of BDNF and TrkB in the regulation of VEGF expression. VEGF mRNA levels in neuroblastoma cells cultured in serum-free media increased after 8 to 16 hours in BDNF. BDNF induced increases in VEGF and HIF-1alpha protein, whereas HIF-1beta levels were unaffected. BDNF induced a 2- to 4-fold increase in VEGF promoter activity, which could be abrogated if the hypoxia response element in the VEGF promoter was mutated. Transfection of HIF-1alpha small interfering RNA blocked BDNF-stimulated increases in VEGF promoter activity and VEGF protein expression. The BDNF-stimulated increases in HIF-1alpha and VEGF expression required TrkB tyrosine kinase activity and were completely blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. These data indicate that BDNF plays a role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to BDNF/TrkB, PI3K, mTOR signal transduction pathways, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.

Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells.

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Understanding the mechanisms regulating VEGF expression in neuroblastoma cells provides additional therapeutic options to control neuroblastoma tumor growth. VEGF mRNA is controlled by growth factors and hypoxia via the transcription factor hypoxia-inducible factor (HIF-1alpha). HIF-1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene, VHL, which targets HIF-1alpha degradation. To determine whether the levels of VEGF in neuroblastomas are due to mutations in VHL, we evaluated genomic DNA from 15 neuroblastoma cell lines using PCR. We found no mutations in exons 1, 2, or 3 of the VHL gene. VEGF mRNA levels in neuroblastoma cells cultured in serum-free medium increased after 8 to 16 hours in serum, insulin-like growth factor-I (IGF-I), epidermal growth factor, or platelet-derived growth factor. Serum/IGF-I induced increases in HIF-1alpha protein that temporally paralleled increases in VEGF mRNA, whereas HIF-1beta levels were unaffected. VEGF and HIF-1alpha levels were blocked by inhibitors of phosphatidylinositol 3-kinase and mammalian target of rapamycin. Furthermore, we confirmed that HIF-1alpha mediates approximately 40% of the growth factor activity stimulating VEGF protein expression. Topotecan blocked the IGF-I-stimulated increase in HIF-1alpha but not HIF-1beta, and this resulted in a decrease in VEGF in four neuroblastoma cell lines tested. These data indicate that growth factors in an autocrine or paracrine manner play a major role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to phosphatidylinositol 3-kinase, mammalian target of rapamycin, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.

Effect of imatinib mesylate on neuroblastoma tumorigenesis and vascular endothelial growth factor expression.

BACKGROUND: Alternative treatment options are needed for advanced neuroblastoma patients because their prognosis remains poor after intensive chemotherapy. Neuroblastoma cells express platelet-derived growth factor (PDGF), stem cell factor (SCF), and vascular endothelial growth factor (VEGF) and their respective receptors, PDGFR, c-Kit, and Flk-1. We therefore evaluated the effects of imatinib mesylate (imatinib), a selective inhibitor of the tyrosine kinase activities of c-Kit and PDGFR, on the growth of neuroblastoma cells in vivo and in vitro. METHODS: We tested seven human neuroblastoma cell lines for their sensitivity to imatinib. Cell viability was assessed by trypan blue dye exclusion. Apoptosis was evaluated by nuclear staining, flow cytometry, and western blotting. Protein assays included immunoprecipitation, western blotting, enzyme-linked immunosorbent assays, and immunohistochemistry. mRNA expression was assessed by northern blotting. We used a xenograft model in SCID mice (10 mice per group) to evaluate the effects of imatinib oral therapy (50 or 100 mg/kg every 12 hours for 14 days) on neuroblastoma tumor growth. All statistical tests were two-sided. RESULTS: All seven neuroblastoma cell lines treated with imatinib displayed concentration-dependent decreases in cell viability, which coincided with an induction of apoptosis, and with ligand-stimulated phosphorylation of c-Kit and PDGFR. The imatinib concentrations that caused 50% inhibition of growth and 50% inhibition of ligand-induced phosphorylation of these receptors were 9-13 micro M and 0.1-0.5 microM, respectively. Expression of VEGF, but not phosphorylation of Flk-1, its receptor, was reduced in neuroblastoma cells treated with imatinib at 10 microM or higher. Mice treated with imatinib at 50 mg/kg or 100 mg/kg had statistically significantly smaller tumors than control mice treated with vehicle (mean tumor volume in mice treated with imatinib at 50 mg/kg = 1546 mm3, in control mice = 2954 mm3; difference = 1408 mm3, 95% confidence interval [CI] = 657 to 2159 mm3; P<.001; mean tumor volume in mice treated with imatinib at 100 mg/kg = 463 mm3; difference = 2491 mm3, 95% CI = 1740 to 3242 mm3; P<.001). CONCLUSIONS: Imatinib inhibited the growth of neuroblastoma cells in vitro and in vivo. This inhibition was associated with suppression of PDGFR and c-Kit phosphorylation and inhibition of VEGF expression.

Inhibition of interferon-gamma-activated nuclear factor-kappa B by cyclosporin A: A possible mechanism for synergistic induction of apoptosis by interferon-gamma and cyclosporin A in gastric carcinoma cells.

We previously reported synergistic induction of apoptosis by IFN-gamma plus either cyclosporin A (CsA) or tacrolimus (FK506) in gastric carcinoma cells. In this study, we aimed to elucidate the mechanism for this synergistic induction of apoptosis. IFN-gamma plus CsA synergistically induced caspase-3 mediated apoptosis in gastric carcinoma cells. Although IFN-gamma induced activation of signal transducer and activator of transcription1 (STAT1) and expression of interferon regulatory factor-1 (IRF-1) mRNA, IFN-gamma alone was not able to induce caspase-3 activation and apoptosis. When gastric carcinoma cells were treated with cyclohexamide, a protein synthesis inhibitor, following IFN-gamma pretreatment, caspase-3 was activated, and apoptosis was markedly induced. These findings suggest the existence of IFN-gamma-induced anti-apoptotic pathway and we evaluated the effect of IFN-gamma and CsA on calcium-sensitive nuclear factor-kappa B (NF-kappa B) activation. IFN-gamma increased intracellular calcium ion concentration ([Ca(2+)](i)) consisting of a spike and a sustained phase, and the latter was completely abrogated by CsA. Activation of NF-kappa B occurred in response to IFN-gamma, and which was markedly inhibited by either CsA or FK506. NF-kappa B decoy also enhanced the cytotoxic effect of IFN-gamma. These results suggest that IFN-gamma may simultaneously induce the STAT1-mediated apoptotic pathway and the anti-apoptotic pathway through calcium-activated NF-kappa B and that inhibition of the latter by CsA may result in dominance of the apoptosis-inducing pathway.