Efficacy and Safety of Caspofungin Treatment in Febrile Neutropenic Patients with Hematological Disorders: A Multicenter Consecutive Case Series.

Introduction Invasive fungal infections have been attracting attention as significant fatal complications in patients with febrile neutropenia (FN) who undergo intensive chemotherapy or hematopoietic stem cell transplantation to treat hematological malignancies. Although clinical trials are already underway in other countries, evidence supporting the use of caspofungin (CAS) in FN patients in Japan is still insufficient. Methods A retrospective study of patients treated with CAS for FN associated with hematological diseases between April 2015 and March 2018 was conducted to determine the treatment efficacy and safety. The study was conducted as a multicenter collaboration, and the data of 52 patients who met all of the inclusion criteria were analyzed. A five-composite-endpoint method was used, and the treatment was judged to be effective when all five endpoints (defervescence during neutropenia; no breakthrough fungal infections; resolution of baseline fungal infections; a survival for seven days or more after the completion of therapy; and no discontinuation of therapy due to side effects or invalidity) were met. Results The efficacy rate was 53.8% (28/52), which is close to the average reported efficacy rate. Adverse events included liver dysfunction and electrolyte abnormalities, but no renal dysfunction or serious events were seen. Conclusion These results suggest that the use of CAS in FN patients with hematological diseases is effective and well-tolerated, and we believe that the use of CAS could become a significant treatment in Japan.

High-dose chemotherapy with autologous stem cell transplantation following systemic chemotherapy, prophylactic intrathecal methotrexate, and radiotherapy prevents relapse and improves the outcome of advanced stage primary testicular lymphoma even with cardiac involvement.

Primary testicular lymphoma (PTL) is a rare but aggressive disease. Although most patients present in the early stage, their prognosis is poor. Similar with PTL, cardiac lymphoma is also an uncommon disease characterized by its aggressive clinical course and poor prognosis. We herein report an extremely rare case of advanced stage PTL with cardiac involvement, treated by high-dose chemotherapy with autologous stem cell transplantation (HDT-ASCT) followed by systemic chemotherapy, prophylactic intrathecal methotrexate (IT-MTX), and radiotherapy. A 48-year-old man presented with painless left scrotal swelling. He was diagnosed with PTL after orchiectomy, and the histological type was diffuse large B-cell lymphoma. For staging of lymphoma, positron emission tomography was performed, which revealed uptake in the right atrium and early cardiac metastasis within just 2 months after orchiectomy. He underwent 6 cycles of systemic chemotherapy that consisted of rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone (R-CHOP). He also received central nervous system prophylaxis 4 times with weekly IT-MTX during the first 2 cycles of R-CHOP. He achieved complete response after 6 cycles of R-CHOP, and underwent HDT-ASCT and radiotherapy as consolidation therapy without irreversible adverse effects. He is currently doing well, with a progression-free survival of 31 months. The above treatment strategy including HDT-ASCT may be one of the treatment options for advanced stage PTL with cardiac metastasis in patients younger than 65 years old.

Achievement of the longest survival of paraneoplastic pemphigus with bronchiolitis obliterans associated with follicular lymphoma using R-CHOP chemotherapy.

Paraneoplastic pemphigus (PNP) is a rare, fatal, paraneoplastic autoimmune mucocutaneous blistering disease, commonly associated with lymphoproliferative disorders, including malignant lymphomas. Lymphoproliferative disorders associated with PNP are sometimes associated with a serious lung complication, bronchiolitis obliterans (BO). Due to its rarity, guidelines for the management of PNP have not been established. Furthermore, most patients die within 1 year. Here we report the successful treatment of lymphoma-associated PNP and BO using R-CHOP chemotherapy. A 53-year-old Japanese man was admitted to our hospital for severe erosive stomatitis. Computed tomography and positron emission tomography showed multiple lymphadenopathies. He was diagnosed with follicular lymphoma (Ann Arbor stage IVA) and PNP-related BO. The patient underwent six cycles of R-CHOP and an additional cycle of rituximab. Both the erosive stomatitis and the obstructive lung disease persisted, but complete response of the follicular lymphoma was achieved. The patient survived 27 months after diagnosis. Although he died from progressive respiratory failure due to BO, we note that this patient achieved the longest survival of any reported case of PNP-related BO associated with a lymphoproliferative disorder. The present case suggests that intensive immunochemotherapy for underlying lymphoma may improve the prognosis in patients with PNP-related BO associated with lymphoma.

Imatinib mesylate inhibits the proliferation-stimulating effect of human lung cancer-associated stromal fibroblasts on lung cancer cells.

Platelet-derived growth factor (PDGF) is a significant mediator in the proliferation of cancer-associated stromal fibroblasts (CAFs). The inhibition of CAF proliferation by blocking PDGF signaling could lead to a development of novel cancer therapy. We analyzed whether inhibiting proliferation of lung CAFs by imatinib mesylate, which has inhibitory activity on PDGF-receptor tyrosine kinase, could suppress the proliferative activity of lung cancer cells which coexisted in the tumor tissue. First, we established primary cultured fibroblasts from human lung cancer tissues. RT-PCR analysis showed that PDGF-receptors (PDGFRalpha and beta) were more highly expressed in the fibroblasts, whereas PDGFs (PDGF-A, and -B) were more in lung cancer cell lines. Western blotting showed that imatinib treatment inhibited phosphorylation of PDGFRbeta, Akt, and Erk1/2 in the fibroblasts. The treatment also significantly inhibited the proliferative activity of the fibroblasts. The inhibitory effects were exerted more definitely in co-administering imatinib and PDGF-BB, a dimer of the polypeptide chains of B, than in administering imatinib alone. The conditioned media of the fibroblasts significantly increased the proliferative activity of human lung cancer cell line A549 compared to control culture medium. The proliferation-stimulating effect on A549 cells decreased significantly in the conditioned media of the primary cultured fibroblasts that had been treated with imatinib. Our results suggest that imatinib has antitumor activity which is exerted by reducing the proliferation-stimulating effect of CAFs on lung cancer cells, as well as inhibiting the proliferation of CAFs, by way of blocking PDGF signaling.

Candin family antifungal agent micafungin (FK463) modulates the inflammatory cytokine production stimulated by lipopolysaccharide in THP-1 cells.

Systemic inflammatory response syndrome (SIRS) and sepsis have been considered forms of hypercytokinemia in critically ill patients and immunocompromized hosts. It has been reported that some antimicrobial agents, including antifungal agents, not only have an antibiotic effect, but also they affect the host's immunological response. Immunofunctional cells, including monocytes and macrophages, were examined to determine whether they are influenced by the newly synthesized candin family antifungal agent micafungin (MCFG) using the human monocytic cell line THP-1 stimulated with lipopolysaccharide (LPS) as a model of hypercytokinetic conditions. LPS-induced production of TNF-alpha (tumor necrosis factor-alpha) and interleukin-8 (IL-8) in THP-1 cells was significantly suppressed dose-dependently by MCFG, although high concentrations of MCFG may reach toxic levels. It was clarified that MCFG inhibits the LPS-induced expression of TNF-alpha in THP-1 cells at the mRNA (messenger ribonucleic acid) level. In conclusion, administration of MCFG had an immunomodulatory effect on the host by reducing levels of TNF-alpha and IL-8. The effectiveness of MCFG in modulating hypercytokinemia is due not only to its direct antifungal effect, but also to the modulation of cytokine production in macrophages that regulates immunological activity and inflammation.

Reduced intensity allogeneic stem cell transplantation for systemic primary amyloidosis refractory to high-dose melphalan.

Complete elimination of the plasma cell dyscrasia is a rational therapeutic goal, as intercepting supply of precursor protein is a necessary condition for a major regression of amyloid deposits. High-dose melphalan with autologous stem cell transplantation has shown the ability to induce complete hematological response (HR) along with recovery of organ dysfunction. However, the rate of HR with this treatment rarely exceeds 40%. We describe here the first known case of successful reduced intensity allogeneic stem cell transplantation (RIST) for a patient with primary amyloidosis complicated with nephrotic syndrome but without cardiac disease, who had obtained only partial HR by high-dose melphalan with autologous stem cell transplantation. RIST may be feasible and be capable of achieving complete HR along with recovery from nephrotic syndrome with acceptable toxicity.

[A pilot study of antibiotic cycling for the treatment of febrile neutropenia patients with hematological diseases].

Two antibiotics recommended by the guideline of Infectious Diseases Society of America (IDSA) were selected for treatment of febrile neutropenia, and these paired antibiotics were changed periodically three times. The clinical efficacy of each antibiotic was retrospectively evaluated at the end of the final period. There was no significant difference about efficacy rate between two kinds of antibiotics in the same sequential period. However, the efficacy rate has been rising and febrile duration has been shortening by degrees. Only a few drug resistant bacteria were recognized by the surveillance culture during antibiotic cycling. Recently, antibiotic cycling therapy has attracted attention especially in the ICU. However, a clinical study of treatment for febrile neutropenia has not been reported. Our trial suggests that cycling therapy may be useful for febrile neutropenia. However, Some deviation in the patients characteristics of each period may affect the result. It seems that further examination is necessary about usefullness of the cycling therapy for febrile neutropenia.